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Previously we showed that the vitamin A metabolite all-trans retinoic acid (atRA) induces synaptic plasticity in acute brain slices prepared from the mouse and human neocortex (Lenz et al., 2021). Depending on the brain region studied, distinct effects of atRA on excitatory and inhibitory neurotransmission have been reported. Here, we used intraperitoneal injections of atRA (10 mg/kg) in adult C57BL/6J mice to study the effects of atRA on excitatory and inhibitory neurotransmission in the mouse fascia dentata—a brain region implicated in memory acquisition. No major changes in synaptic transmission were observed in the ventral hippocampus while a significant increase in both spontaneous excitatory postsynaptic current frequencies and synapse numbers were evident in the dorsal hippocampus 6 hr after atRA administration. The intrinsic properties of hippocampal dentate granule cells were not significantly different and hippocampal transcriptome analysis revealed no essential neuronal changes upon atRA treatment. In light of these findings, we tested for the metaplastic effects of atRA, that is, for its ability to modulate synaptic plasticity expression in the absence of major changes in baseline synaptic strength. Indeed, in vivo long-term potentiation (LTP) experiments demonstrated that systemic atRA treatment improves the ability of dentate granule cells to express LTP. The plasticity-promoting effects of atRA were not observed in synaptopodin-deficient mice, therefore, extending our previous results regarding the relevance of synaptopodin in atRA-mediated synaptic strengthening in the mouse prefrontal cortex. Taken together, our data show that atRA mediates synaptopodin-dependent metaplasticity in mouse dentate granule cells.

Lewy body disorders are characterized by the emergence of α-synucleinopathy in many parts of the central and peripheral nervous systems, including in the telencephalon. Dense α-synuclein+ pathology appears in regio inferior of the hippocampus in both Parkinson’s disease and dementia with Lewy bodies and may disturb cognitive function. The preformed α-synuclein fibril model of Parkinson’s disease is growing in use, given its potential for seeding the self-propagating spread of α-synucleinopathy throughout the mammalian brain. Although it is often assumed that the spread occurs through neuroanatomical connections, this is generally not examined vis-à-vis the uptake and transport of tract-tracers infused at precisely the same stereotaxic coordinates. As the neuronal connections of the hippocampus are historically well defined, we examined the first-order spread of α-synucleinopathy three months following fibril infusions centered in the mouse regio inferior (CA2 + CA3), and contrasted this to retrograde and anterograde transport of the established tract-tracers FluoroGold and biotinylated dextran amines (BDA). Massive hippocampal α-synucleinopathy was insufficient to elicit memory deficits or loss of cells and synaptic markers in this model of early disease processes. However, dense α-synuclein+ inclusions in the fascia dentata were negatively correlated with memory capacity. A modest compensatory increase in synaptophysin was evident in the stratum radiatum of cornu Ammonis in fibril-infused animals, and synaptophysin expression correlated inversely with memory function in fibril but not PBS-infused mice. No changes in synapsin I/II expression were observed. The spread of α-synucleinopathy was somewhat, but not entirely consistent with FluoroGold and BDA axonal transport, suggesting that variables other than innervation density also contribute to the materialization of α-synucleinopathy. For example, layer II entorhinal neurons of the perforant pathway exhibited somal α-synuclein+ inclusions as well as retrogradely labeled FluoroGold+ somata. However, some afferent brain regions displayed dense retrograde FluoroGold label and no α-synuclein+ inclusions (e.g. medial septum/diagonal band), supporting the selective vulnerability hypothesis. The pattern of inclusions on the contralateral side was consistent with specific spread through commissural connections (e.g. stratum pyramidale of CA3), but again, not all commissural projections exhibited α-synucleinopathy (e.g. hilar mossy cells). The topographical extent of inclusions is displayed here in high-resolution images that afford viewers a rich opportunity to dissect the potential spread of pathology through neural circuitry. Finally, the results of this expository study were leveraged to highlight the challenges and limitations of working with preformed α-synuclein fibrils.

The hippocampal complex, an anatomical composite of several subregions, is known to decrease in size with increasing age. However, studies investigating which subregions are particularly prone to age-related tissue loss revealed conflicting findings. Possible reasons for such inconsistencies may reflect differences between studies in terms of the cohorts examined or techniques applied to define and measure hippocampal subregions. In the present study, we enhanced conventional MR-based information with microscopically defined cytoarchitectonic probabilities to investigate aging effects on the hippocampal complex in a carefully selected sample of 96 healthy subjects (48 males/48 females) aged 18–69 years. We observed significant negative correlations between age and volumes of the cornu ammonis, fascia dentata, subiculum, and hippocampal-amygdaloid transition area, but not the entorhinal cortex. The estimated age-related annual atrophy rates were most pronounced in the left and right subiculum with −0.23% and −0.22%, respectively. These findings suggest age-related atrophy of the hippocampal complex overall, but with differential effects in its subregions. If confirmed in future studies, such region-specific information may prove useful for the assessment of diseases and disorders known to modulate age-related hippocampal volume loss.

We investigated structural changes in the Wistar rat hippocampal CA1 field and fascia dentate during the pubertal period (on P60) after perinatal hypoxic exposure as well as the distribution of GAD67-expressing neurons in these structures. It was established that in the granular layer of the fascia dentata and in the CA1 field acute perinatal hypoxia leads to irreversible homotypic abnormalities as expressed in the reduced number of neurons and their rows as well as injury of a considerable portion of cells, which exhibit the signs of chromatolysis and vacuolization of the cytoplasm. Both in experimental and control animals, GAD67-expressing neurons in the fascia dentata are scattered diffusely and share approximately the same size of their populations. In the CA1 field, immunoreactive neurons lie in the lower rows of the pyramidal layer, while neurons in the upper layers exhibit no immunolabeling and have less synaptic structures in experimental animals than in control. We suggest that neurons in the hippocampal structures are involved in the regulation of functions and formation of prenatal pathology.

Brain structure & function 225, 881-907 (2020). doi:10.1007/s00429-019-02022-4, Published by Springer, Berlin ; Heidelberg

Because of the central role of the hippocampus in representing spatial and temporal details of experience, comparative studies of its volume and structure are relevant to understanding the evolution of representational memory across species. The hippocampal formation, however, is organized into separate anatomical subregions with distinct functions, and little is known about the evolutionary diversification of these subregions. We investigate relative volumetric changes in hippocampal subregions across a large sample of primate species. We then compare the evolution of the hippocampal formation to the neocortex. Results across hippocampal subregions indicate that, compared to strepsirrhines, the anthropoid lineage displays a decrease in relative CA3, fascia dentata, subiculum, and rhinal cortex volume in tandem with an increase in relative neocortical volume. These findings indicate that hippocampal function in anthropoids might be substantially augmented by the executive decision-making functions of the neocortex. Humans are found to have a unique cerebral organization combining increased relative CA3, subiculum, and rhinal cortex with increased relative neocortical volumes, suggesting that these regions may play a role in behaviors that are uniquely specialized in humans.

Detailed knowledge about the neural circuitry connecting the hippocampus and entorhinal cortex is necessary to understand how this system contributes to spatial navigation and episodic memory. The two principal cell types of the dentate gyrus, mossy cells and granule cells, are interconnected in a positive feedback loop, by which mossy cells can influence information passing from the entorhinal cortex via granule cells to hippocampal pyramidal cells. Mossy cells, like CA3 pyramidal cells, are characterized by thorny excrescences on their proximal dendrites, postsynaptic to giant terminals of granule cell axons. In addition to disynaptic input from the entorhinal cortex and perforant path via granule cells, mossy cells may also receive monosynaptic input from the perforant path via special dendrites ascending to the molecular layer. We here report qualitative and quantitative descriptions of Golgi-stained hippocampal mossy cells in mink, based on light microscopic observations and three-dimensional reconstructions. The main focus is on the location, branching pattern, and length of dendrites, particularly those ascending to the granular and molecular layers. In mink, the latter dendrites are more numerous than in rat, but fewer than in primates. They form on average 12% (and up to 29%) of the total dendritic length, and appear to cover the terminal fields of both the lateral and medial perforant paths. In further contrast to rat, the main mossy cell dendrites in mink branch more extensively with distal dendrites encroaching upon the CA3 field. The dendritic arbors extend both along and across the septotemporal axis of the dentate gyrus, not conforming to the lamellar pattern of the hippocampus. The findings suggest that the afferent input to the mossy cells becomes more complex in species closer to primates.

– This article deals with the efferent connections of the hippocampal region, and considers the functional implications of these projections. The hippocampus receives indirect sensory information from many structures in the brain. Most of these afferents terminate in the superficial layers (I-III) of the entorhinal area. From cells in layers II and III of entorhinal area projections arise which terminate in hippocampus and fascia dentata, the perforant paths. Internal hippocampal projections constitute a unidirectional system of connections which project back to the deep layers (IV-VI) of the entorhinal area. The efferents from these layers may be divided into cortically terminating efferents, which originate from layer IV, and subcortically terminating efferents, which originate from layers V and VI. The cortically terminating projections end in regions of association cortex, and in limbic cortex. The subcortical projections terminate in the caudate, the putamen, and the accumbens nucleus. A hippocampal influence on these subcortical structures may seem surprising, but is logical when one takes into consideration reports on the functional associations between the striatum and the hippocampus. The findings suggest that the role of the hippocampus may be to gather input from all sensory modalities, to assign priorities continuously between these inputs, and as a result, to modify behavior via its influence on subcortical motor centres.

Summary Purpose: To evaluate the clinical and hippocampal histological features of patients with mesial temporal lobe epilepsy (MTLE) in both familial (FMTLE) and sporadic (SMTLE) forms. Methods: Patients with FMTLE (n = 20) and SMTLE (n = 39) who underwent surgical treatment for refractory seizures were studied at the University of Sao Paulo School of Medicine at Ribeirao Preto. FMTLE was defined when at least two individuals in a family had clinical diagnosis of MTLE. Hippocampi from all patients were processed for Nissl/HE and Timm's stainings. Both groups were compared for clinical variables, hippocampal cell densities, and intensity of supragranular mossy fiber staining. Results: There were no significant differences between FMTLE and SMTLE groups in the following: age at the surgery, age of first usual epileptic seizure, history of initial precipitating injury (IPI), age of IPI, latent period, ictal and interictal video-EEG patterns, presence of hippocampal atrophy and signal changes at MRI, and postoperative outcome. In addition, no differences were found in cell densities in hippocampal cornu ammonis subfields (CA1, CA2, CA3, CA4), fascia dentata, polymorphic region, subiculum, prosubiculum, and presubiculum. However, patients with SMTLE had greater intensity of mossy fiber Timm's staining in the fascia dentata-inner molecular layer (p< 0.05). Discussion: Patients with intractable FMTLE present a clinical profile and most histological findings comparable to patients with SMTLE. Interestingly, mossy fiber sprouting was less pronounced in patients with FMTLE, suggesting that, when compared to SMTLE, patients with FMTLE respond differently to plastic changes plausibly induced by cell loss, neuronal deafferentation, or epileptic seizures.

Summary Purpose: To determine whether hippocampal sclerosis might form an anatomical substrate for pathological high-frequency oscillations in patients with temporal lobe epilepsy (TLE). Methods: Intracerebral wide bandwidth electroencephalogram was recorded in patients with medically intractable complex partial seizures. A computer-automated program detected interictal normal ripples (80–150 Hz) and pathologic fast ripples (FR, 151–500 Hz) from microelectrodes within hippocampus, entorhinal, and subicular cortices. Hippocampal MRI volumetric analysis and cell density measurements were correlated with rates of FR and ripple discharge. Results: In all 13 patients, higher rates of FR (p = 0.03) and ratios of FR to ripple discharges (p = 0.02) were observed in sites ipsilateral to seizure onset compared with rates within contralateral nonictal sites. Higher ratios of FR to ripple discharge were associated with smaller ipsilateral hippocampal volumes (p = 0.02) and lower fascia dentata (FD; p = 0.02) and Ammon's horn (p = 0.0005) neuron densities. While reduced FD and Ammon's horn neuron densities correlated with higher ratios of discharges, stepwise multiple regression analysis revealed that decreased neuron densities within CA1 and prosubiculum regions most strongly predicted ratios of FR to ripples (r2= 0.78, p = 0.008). Conclusions: In surgical patients with TLE, higher ratios of FR to ripple discharges are associated with histopathologic changes found in hippocampal sclerosis. These findings support the hypothesis that pathological alterations linked with hippocampal cell loss and synaptic reorganization promote FR and reduce ripple generation.

epilepsy and so far nothing regarding to HSP90. Due to the probable HSP70 protective role and the HSP90 relation with key-factor proteins in epileptogenesis, we looked at HSP70 and HSP90 immunohistochemical expression in temporal lobe epilepsy (TLE). Methods: 47 hippocampi were obtained from medically intractable TLE patients: 16 TLE, 18 TLE+depression and 13 TLE+psychosis. 6 control hippocampi were from necropsy cases without past history of neurological disorders, with pos-mortem delay no longer than 4 hours. Specimens were equally treated and submitted to imunohistochemistry to HSP70 and HSP90. Hippocampal regions examined were fascia dentata, hilum, CA4, CA3, CA2, CA1, prosubiculum, subiculum, parahippocampal gyrus and entorhinal cortex. Positive immunoreactivity (puncta) was estimated using the software ImageJ. Results: Analyzes of variancy (ANOVA) of our results showed significant differences. Dunn’s post-hoc tests (p < 0.05) of our ANOVA showed significant lower expression of HSP70 and HSP90 in epileptic patients when compared to controls in all hippocampal regions, except fascia dentata and subiculum. Regarding HSP70, the same occurred in all subicular subfields. As to HSP90, there are also differences between TLE+depression and TLE+psychosis at hilum, prosubiculum and hippocampal gyrus. TLE+psychosis always showed values closed to controls. Conclusions: Unlike the reports in animal models the present results indicate that chronic seizures in TLE patients are not sufficient to induce HSP70 and HSP90 activation. Neuronal loss, gliosis and synaptic reorganization, which are typical attributes of TLE, may be determinants of low HSP expression. Inherent to our findings and conclusions, it is important to notice methodological differences between experimental and control groups. Although an effort was made to include only necropsy patients with short post mortem delay, the cause of patients death could be, at least partially, responsible to some degree of HSP activation. Nevertheless, the neurological complications on this group led us to suggest that low expression of HSPs in epileptic groups is related to seizure maintenance. We found no explanation for the differential HSP90 expression in TLE patients with psychosis. (Supported by Fapesp (CInAPCe project # 05/56447–7), CNPq and FAEPA.)

The entorhinal cortex gives rise to a massive projection to the hippocampus and fascia dentata. In the rat, this projection forms early in development with first entorhinal axons reaching the hippocampus around embryonic day (E) 17. From the very beginning, the entorhinal axons recognize their appropriate termination zones in the hippocampus proper and fascia dentata, i.e., stratum lacunosum-moleculare and the outer molecular layer of the dentate. This is remarkable, because at the time of entorhinal fiber ingrowth, the definitive target cells of entorhinal axons, pyramidal cells and granule cells, are not yet fully developed, and the majority of their distal dendritic tips have not yet reached these layers. This raises the question as to the cellular and molecular signals guiding the entorhinal axons to and keeping them in their target layers. Here we hypothesize that early generated Cajal-Retzius (CR) cells located in stratum lacunosum-moleculare and the outer molecular layer of the dentate, and in particular their axons projecting to the entorhinal cortex, provide a template that is used by the entorhinal axons to find their target layers in the hippocampus.

The Ts65Dn mouse is a genetic model for Down syndrome. Although this mouse shows abnormalities in cognitive function that implicate hippocampus as well as marked deficits in hippocampal long-term potentiation, the structure of the hippocampus has been little studied. We characterized synaptic structure in Ts65Dn and control (2N) mice, studying the hippocampus (fascia dentata, CA1) as well as the motor and somatosensory cortex, entorhinal cortex, and medial septum. Confocal microscopy was used to examine immunostained presynaptic boutons and to detail the structure of dendrites after Lucifer yellow microinjection. Both presynaptic and postsynaptic elements were significantly enlarged in Ts65Dn in all regions examined. The changes were detected at the youngest age examined (postnatal day 21) and in adults. In studies detailing the changes in fascia dentata and motor cortex, the enlargement of spines affected the entire population, resulting in the presence of spines whose volume was greatly increased. Electron microscopy confirmed that boutons and spines were enlarged and demonstrated abnormalities in the internal membranes of both. In addition, spine density was decreased on the dendrites of dentate granule cells, and there was reorganization of inhibitory inputs, with a relative decrease in inputs to dendrite shafts and an increase in inputs to the necks of spines. Taken together, the findings document widespread abnormalities of synaptic structure that recapitulate important features seen in Down syndrome. They establish the Ts65Dn mouse as a model for abnormal synapse structure and function in Down syndrome and point to the importance of studies to elucidate the mechanisms responsible for synapse enlargement. J. Comp. Neurol. 480:281–298, 2004. © 2004 Wiley-Liss, Inc.

The hippocampus, in the temporal lobe, is phylogenetically one of the oldest parts of the brain and forms part of the limbic system. The hippocampus proper is defined by the dentate gyrus and Cornu Ammonis (CA). While the dentate gyrus contains the fascia dentata and the hilus, the CA is anatomically and functionally differentiated into distinct subfields named CA1, CA2, CA3, and CA4. The CA3 region has attracted major attention in recent years for its specific role in memory processes, susceptibility to seizures and neuro-degeneration. Internal connectivity in the CA3 subfield is more rich than in other hippocampal regions. Recurrent axon collaterals of CA3 pyramidal cells ramify extensively making excitatory contacts with neighboring excitatory and inhibitory neurons (Lorente de No, 1934). This circuit is implicated in encoding spatial representations (O'Keefe and Nadel, 1978) and episodic memories (Scoville and Milner, 1957). It generates coherent population synchronies, including gamma, theta and sharp-waves, presumed to associate firing in selected assemblies of cells in different behavioral conditions (Buzsaki et al., 1983). The CA3 region receives inputs from the entorhinal cortex either directly via the perforant path or indirectly from the dentate gyrus via the mossy fibers (Amaral and Witter, 1983). Mossy fiber connections made with principal or mossy cells terminate with large boutons (5–8 μm) while those with interneurons are targeted by smaller filopodial extensions. The mossy fiber pathway acts as a high-pass filter that translates densely coded cortical signals to a sparse, specific hippocampal code, essential for memory formation. This e-book aims to highlight recent advances by bringing together experts on the cellular and molecular mechanisms regulating the wiring properties of the CA3 hippocampal microcircuit in both physiological and pathological conditions. The seven reviews and four research articles are organized to follow neuronal information flowing from the dentate gyrus to the CA3 associative network. Firstly, Munster-Wandowski et al. (2013) (Inst. Integrative Neuroanatomy, La Charite, Berlin and Instituto Politecnico Nacional, Mexico City) review recent data showing that MF terminals can transiently release GABA as well as glutamate, both in early post-natal life and after periods of intense activity in adulthood. GABA and glutamate co-release from single identified MF boutons has been recently demonstrated. Mossy fibers apparently form electrical synapses, as well as chemical synapses, with CA3 pyramidal cells potentially permitting a fast excitation to overcome a strong, but delayed, feed-forward inhibition. Since MF axons of dentate granule cells may be generated post-natally, Pedroni et al. (2014) (Dept. Neurosci, SISSA, Trieste and European Brain Research Inst, Rome) studied immature granule cells at P0–P3. At this age, with a clear GABAergic phenotype, granule cells have small somata, few dendritic branches and axons often terminate as growth cones in the CA3 region. Depolarization induces either rudimentary or overshooting sodium spikes and low threshold calcium spikes. Post-synaptic CA3 pyramidal cells participate in spontaneous GDPs driven by synergistic actions of GABA and glutamate. The excitatory actions of GABA released from mossy fiber terminals may be crucial for network synchrony, suggested to refine microcircuits of the CA3 region. Radial glial cells guide migrating CA3 neurons during development. After characterizing signaling molecules and the temporal sequence of hippocampal development, Belvindrah et al. (2014) (INSERM U839, Inst. Fer a Moulin, Paris) review abnormalities of migration linked to human brain malformations: agenesia, lissencephaly, holoprosencephaly, polymicrogyria, heterotopia, and focal cortical dysplasia. Mutations in genes associated with neuronal migration in mouse models result in lamination defects of the CA3 area, a region especially vulnerable to stress and seizure-induced damage. This review links genetic, migration and cellular defects and multiple inherited neurological and psychiatric disorders. An overview of how CA3 neurons process afferent activity from dentate granule cells is provided by Evstratova and Toth (2014) (Dept. Psychiatry and Neuroscience, Universite Laval, Quebec City). They describe how the shape of mossy fiber terminals affects transmission to both CA3 pyramidal cells and interneurons. Transmission exhibits short-term plasticities over different frequencies which vary according to post-synaptic cell type. Granule cells usually fire at 0.01–0.1 Hz, but frequency can increase to 15–50 Hz or even higher when spatial information is coded. At these higher frequencies, glutamate also activates presynaptic autoreceptors, which modulate calcium signaling and release from mossy fiber terminals. These processes, including synaptic plasticity, differ at MF. Lorente de No (1934) suggested that recurrent cortical connections might underly reverberating neuronal discharges as a short-term electrical memory. Le Duigou et al. (2014) (INSERM U112, Inst. du Cerveau et de la Moelle, Paris) review recurrent circuits in the CA3 region. CA3 pyramidal cell axons form an associative network associated with sharp waves and other EEG oscillations as well as epileptiform synchrony. Paired records from CA3 pyramidal cells and interneurons have provided data on synaptic contacts and efficacy within recurrent circuits. Connectivity in the associative recurrent CA3 network seems to be spatially more extensive and sparse than in other sensory cortices possibly facilitating representation coding. Kesner (2013) (Dept. Psychology, Univ. Utah, Salt Lake City) reviews contributions from the CA3 region subfields CA3a, b and c in acquiring and encoding spatial information. Mnemonic functions depend on synaptic interactions of CA3 associative networks, operating as an attractor, with inputs from the dentate gyrus and entorhinal cortex (Kesner and Hunsaker, 2010). Fields CA3a and b encode spatial information in short-term memory and also support retrieval by spatial pattern completion. In contrast, the CA3c field may support pattern separation via interactions with the DG. The output subfields, CA3a and b process information sequentially communicating with the CA1 region via the Schaffer collaterals. Rolls (2013) (Centre for Computational Neuroscience, Univ Oxford and Dept. Computer Science, Univ. Warwick) describes quantitatively how the CA3 region operates and how it contributes to episodic memory. The CA3 system, through its recurrent collateral connections, is presented as a single attractor enabling fast, one trial, associations between any spatial location and an object or reward. A recurrent structure permits memory completion during recall from any subset of acquired links. This theory permits associations between time, objects and rewards to provide the temporal order needed for episodic memory. Neurophysiological tests and supports of the theory are described with novel hypotheses on the advantages of a low recurrent connectivity in CA3. Cerasti and Treves (2013) (Cognitive Neuroscience, SISSA, Trieste, College de France, Paris and Kavli Inst., Trondheim) next discuss how self-organizing recurrent connections enable spatial representations to be acquired in the CA3 area. A simplified network model shows that self-organization can lead to the emergence of multiple loosely organized discrete point-like attractors which differ from structures associated with a single, continuous attractor. The pivotal role of the CA3 region in humans is discussed by Deuker et al. (2014) (Dept. Epileptology and Center for Neurodegenerative Diseases Univ. Bonn and Donders Inst., Univ. Nijmegen). They describe how the human CA3 region forms associations during encoding and how during retrieval it reconstructs memory representations with pattern separation and completion based on partial cues (Deuker et al., 2013). Functional properties of different hippocampal subfields can be identified with high resolution fMRI and related to behavioral, and structural alterations associated with mild cognitive impairment in early Alzheimer's disease. Spatial information is encoded by the phase of principal cell firing during theta oscillations. The hyperpolarization activated cation current Ih is a critical regulator of this phase dependent firing. The research article of Borel et al. (2013) (Dept. Physiology, Development and Neuroscience, Univ. Cambridge and Dept. Brain and Cognitive Engineering, Korea Univ. Seoul) asks how Ih controls firing of CA1 and CA3 pyramidal cells. CA1 neurons are suggested to express Ih at higher levels than CA3 pyramidal cells ensuring larger responses to hyperpolarization and thus more prominent resonance peaks. With a strong Ih, excitatory inputs during theta can delay firing, an effect counteracted by phasic inhibitory currents during theta oscillations. Interactions between synaptic inputs and active Ih currents may then account for distinct phase responses of CA1 and CA3 neurons in temporal outputs during theta oscillations. The final article from Nava-Mesa et al. (2013) (Lab. Neurofisiologia y Comportamiento, Univ. Castilla-La Mancha, Ciudad Real and Dept. Fisiologia y Farmacologia, Univ. Salamanca) shows how the Aβ peptide affects synapses made by fimbrial afferents with CA3 pyramidal cells. Stimulation of the lateral fimbria evokes AMPA-mediated EPSPs followed by early and late IPSPs mediated by distinct GABA receptors. Aβ depolarizes CA3 pyramidal cells, increases their input resistance and decreases the late GABAB-mediated IPSP current. This post-synaptic effect, is mediated via the G protein-gated inwardly rectifying potassium channel GirK. Dysfunction of septo-hippocampal oscillations involving GirK at fimbria-CA3 synapses may account for memory deficits during early stages of Alzheimer's disease.

The hippocampus is part of the limbic system which mediates emotions and aspects of learning and memory. In the rat, it is a rostro-caudal structure whereas in primates it is strictly localized in the temporal lobe. The hippocampus is composed of two interconnected crescent-like regions: the Ammon’s horn (cornu ammonis) and the dentate gyrus (DG, also called fascia dentata). On a coronal section, Ammon’s horn of the rodent can be further subdivided into three regions, CA1, CA2 and CA3 (CA for cornu ammonis). In humans, another subdivision exists, CA4, which is located between the two bands of the dentate gyrus. Ammon’s horn and dentate gyrus both contain a layer of principal neurons that are projection neurons (Golgi type I): the pyramidal cell layer and the granular cell layer, respectively. Numerous local interneurons (Golgi type II) are present in each region. Principal cells use glutamate as a neurotransmitter whereas interneurons use GABA.

Summary: Purpose: Nitric oxide (NO) has been implicated in a variety of functions, including the control of synaptic plasticity and sensory signaling. Current evidence suggests that this unconventional neurotransmitter mediates N-methyl-d-aspartate (NMDA) receptor–linked excitotoxicity. This study describes the expression of neuronal NO synthase (nNOS) immunoreactivity (IR) in hippocampi from patients with temporal lobe epilepsy (TLE). Methods: Hippocampi from patients with clinical symptoms, neuroimaging, and EEG typical of hippocampal sclerosis (HS; n = 22) were compared with those from patients with neocortical temporal lesions (NONHS; n = 4) and autopsy (AUT; n = 18) patients for total cells, and nNOS-IR neuron and puncta densities. Results: Compared with AUT, HS hippocampi had significantly less nNOS-IR neuron densities in the fascia dentata (FD); hilus, and CA4, CA3, CA2, and CA1 subfields. HS hippocampi had significantly greater nNOS-IR puncta densities in the FD, as compared with AUT and NONHS. Conclusions: Our results show that hippocampi from TLE patients exhibit a loss of nNOS-IR neurons and an abnormal FD innervation. The release of NO can influence the dynamics of ionic channels and neurotransmitter release, thus affecting neuronal membrane potential. Because the NOergic transmission does not obey the topographic constraints imposed on conventional transmitters, target cells can be stimulated even in regions with severe deafferentation. The plastic changes described here may contribute to abnormal hippocampal excitability.

In Alzheimer's disease (AD), changes in dendritic morphology can be regarded as a result of an inherent disease-specific process associated with the formation of neurofibrillary tangles. Using three-dimensional morphometrical techniques and neuropatholologically staged tissue (Braak classification) of 32 cases, we demonstrate alterations in the dendritic length, branch order and number of segments of a tangle-free neuronal population in the AD-afflicted hippocampus, i.e. parvalbumin-containing cells of the fascia dentata. These alterations occurred primarily on the apical dendritic tree, the target of the entorhinal input. Mean of relative dendritic length, branch order and number of dendritic segments of apical dendrites decreased significantly, by 40-70% comparing stage V to stages 0 or I. In contrast, basal dendrites receiving no entorhinal input did not show significant changes. Entorhinal neurons projecting to the hippocampus are the first to be affected in AD and the first to die, resulting in hippocampal deafferentation. Therefore, this input-specific dendritic alteration of tangle-free neurons suggests that AD is confounded with a transneuronal component resulting from deafferentation. Experiments showed that deafferentation results in altered dendritic geometry causing an impaired signal integration. Thus, transneuronally altered dendritic signal integration might occur in neurons devoid of the major intraneuronal hallmark of AD, i.e. the neurofibrillary tangle.

The medial cerebral cortex of lizards, an area homologous to the hippocampal fascia dentata, shows delayed postnatal neurogenesis, i.e., cells in the medial cortex ependyma proliferate and give rise to immature neurons, which migrate to the cell layer. There, recruited neurons differentiate and give rise to zinc containing axons directed to the rest of cortical areas, thus resulting in a continuous growth of the medial cortex and its zinc-enriched axonal projection. This happens along the lizard life span, even in adult lizards, thus allowing one of their most important characteristics: neuronal regeneration. Experiments in our laboratory have shown that chemical lesion of the medial cortex (affecting up to 95% of its neurons) results in a cascade of events: first, massive neuronal death and axonal-dendritic retraction and, secondly, triggered ependymal-neuroblast proliferation and subsequent neo-histogenesis and regeneration of an almost new medial cortex, indistinguishable from a normal undamaged one. This is the only case to our knowledge of the regeneration of an amniote central nervous centre by new neuron production and neo-histogenesis. Thus the lizard cerebral cortex is a good model to study neuronal regeneration and the complex factors that regulate its neurogenetic, migratory and neo-synaptogenetic events.O córtex cerebral de lagartos, uma área homóloga à fascia dentata hipocampal, exibe neurogênese pós-natal prolongada, isto é, o epêndima do córtex medial prolifera e dá origem a neurônios imaturos, que migram para a camada celular. Nesta camada, neurônios recrutados se diferenciam e dão origem a axônios, ricos em zinco, que se projetam para as demais áreas corticais, do que resulta um crescimento contínuo do córtex medial e sua projeção axonal. Isto acontece por toda a vida do lagarto, mesmo em animais adultos, o que permite uma de suas características mais importantes: a regeneração neuronal. Experimentos em nosso laboratório demonstraram que uma lesão química do córtex medial (afetando até 95% de seus neurônios) resulta em uma cascata de eventos: inicialmente, morte celular e retração dendro-dendrítica maciças, seguidas de proliferação neuroblasto-ependimária e subseqüente neo-histogênese e regeneração de um novo córtex medial, indistingüível de um normal, não danificado. Ao que saibamos, este é o único caso de regeneração de uma estrutura nervosa central por produção de novos neurônios e neo-histogênese em amniotas. Portanto, o córtex cerebral do lagarto é um bom modelo para estudar a regeneração de neurônios e os fatores complexos que regulam os seus eventos neurogenéticos, migratórios e de neo-sinaptogênese.

We used in situ hybridization techniques to study the distribution of neurones synthesizing somatostatin mRNA and neuropeptide Y mRNA in the hilar region of the hippocampal formation of patients with temporal lobe epilepsy. In the dentate gyrus, somatostatin mRNA- and neuropeptide Y mRNA-synthesizing neurones were found to be exclusively located within the hilar region. Unlike animal models, no ectopic expression of either peptide was found in principal cells. The numbers of hilar interneurones expressing somatostatin mRNA and neuropeptide Y mRNA were compared with the degree of hilar cell loss determined by immunohistochemistry against neuronal nuclear antigen. The numbers of somatostatin and neuropeptide Y mRNA-synthesizing neurones varied considerably between patients, but both were found to be highly correlated to the total number of neuronal nuclear antigen-immunoreactive hilar neurones. These results suggest that loss of somatostatin and neuropeptide Y interneurones occurs in proportion to overall hilar cell loss, and therefore the hypothesis of a selective loss of these interneurones in temporal lobe epilepsy seems unlikely.

The hippocampal formation is a neuroanatomically well-defined region of the brain involved in memory processes. In view of the functional importance of the region and its involvement in a number of brain pathologies, including Alzheimer's disease and temporal lobe epilepsy, a quantitative description of its vascular supply represents an important first step in evaluating the involvement of vascular changes in these phenomena. Unbiased estimates of the length and connectivity of the vascular supply of brain regions have not been described previously. The total number, total length, and distribution of the diameters of capillaries were estimated in the five major subdivisions of the hippocampal formation (fascia dentata, hilus, CA3-2, CA1, and subiculum) in 5 normal males, 52–84 years of age. These estimates were used to derive several other structural parameters. Both the primary and the derived parameters were used to make inter- and intra-individual comparisons. For each of the five major subdivisions from each individual, the volume was estimated using the Cavalieri principle. The total capillary length was estimated on 3-μm-thick plastic isotropic uniform random sections. Using a topological definition of a capillary unit and the optical disector, total capillary number was estimated in 40-μm-thick plastic sections. Length- and number-weighted three-dimensional diameter distributions were obtained from the thin and thick plastic sections, respectively. In each subdivision the total length of capillaries was correlated with previously obtained data on the number of neurons in the same subdivisions of the same individuals. Intersubdivisional differences were observed, in that the hilus of the dentate gyrus had fewer capillaries per unit volume than the other four subdivisions. Interindividual comparisons indicate that the interindividual variances are of a magnitude suitable for sensitive group comparisons. The design-based stereological methods that were used in the analyses can provide a basis for a new unbiased approach to the estimation of vascular parameters in well-defined regions of the brain. Hippocampus 2001;11:726–740. © 2001 Wiley-Liss, Inc.

The effects of hippocampal treatment with a phosphorothioate oligodeoxynucleotide (ODN) antisense to the γ-aminobutyric acid (GABA) A receptor γ2 subunit on neuropeptide Y (NPY) were studied. Adult male Wistar rats were treated with unilateral intrahippocampal infusion of γ2 subunit antisense ODN for 5 days. Rats infused with mismatch ODN and naive rats served as controls. Brain sections were analysed for levels of NPY mRNA by in situ hybridisation, NPY-immunoreactivity (NPY-ir) by means of immunocytochemistry, and specific NPY binding sites by in vitro receptor autoradiography. Following infusion of antisense ODN, a marked increase in cytoplasmic NPY-ir was observed in hilar neurones of the fascia dentata. Further, intense NPY-ir was visualised in the mossy fibres and in cell bodies of the entorhinal cortex and throughout the neocortex. High levels of NPY mRNA were detected in the same cortical areas of antisense treated rats. A very large increase was observed in the piriform and parietal areas. NPY gene expression also occurred in the granular cell layer, in which no NPY mRNA could be detected in normal animals. The level and distribution of cells displaying high levels of NPY mRNA differed among animals, perhaps as a result of the distinct anatomical location of ODN infusion. Finally, hippocampal levels of NPY specific binding increased, suggesting that NPY neurotransmission is markedly increased. These findings are reminiscent of reported changes in the expression of NPY mRNA and immunoreactivity in conditions of increased neuronal excitation and support the usefulness of the present animal model for the study of epileptic phenomena.

A modulatory role for the hippocampal theta rhythm in synaptic plasticity is suggested by the observations that theta occurs during exploratory behaviors, spatial learning is impaired when the theta rhythm is disrupted, and excitation of hippocampal principal cells is phase-coupled to the theta wave. The theta phase affects the nature of the plasticity induced in urethane-anesthetized rats and in the carbachol-treated in vitro slice preparation, but these oscillations are phenomenologically different from natural theta, and the effects of theta phase on plasticity under natural conditions have not been reported. We therefore examined the effects of theta phase on the magnitude of long-term potentiation (LTP) in awake rats running on a linear track for a food reward. Twelve adult and 10 aged F344 male rats were implanted with a stimulating electrode in the perforant path and a recording electrode in the hilus of the fascia dentata. Stimuli were delivered at the peak or trough of the hilar theta rhythm. In both adult and aged, memory-impaired rats, LTP lasting at least 48 h was induced when stimuli were delivered at the positive theta peak, whereas LTP was not induced when stimuli were delivered at the negative troughs. Consistent with the finding that the threshold for LTP induction is increased at this synapse in old rats, the magnitude of LTP induced at the peak of theta rhythm was significantly lower in old animals. These data confirm that LTP can be modulated by locomotion-induced theta, and that this modulation is at least qualitatively preserved across age.

Background: Several studies suggest that neurocysticercosis is the main cause of symptomatic epilepsy in developing countries. In such areas, calcified cysticercotic lesions (CCL) are frequently found in patients with complex partial seizures associated with hippocampal sclerosis (HS). The authors studied whether there are clinical and pathologic differences between HS patients with and without CCL. Methods: The authors determined the clinical and pathologic findings of 30 patients with HS and compared them with 32 patients with HS + CCL. Hippocampi from both groups were measured for fascia dentata Timm staining and cell density in hippocampal subfields. Results: In the HS + CCL group, single or multiple CCL were found in all lobes with no lobar predominance. An initial precipitating event occurred in 83.3% of HS and in 62.5% of HS + CCL. First complex partial seizure occurred at 10.1 years in HS and at 11.9 years in HS + CCL. No significant differences were found for fascia dentata Timm staining and hippocampal cell densities. Good postsurgery outcome (Engel I classification) did not differ between groups, with this result occurring in 76.6% of patients with HS and 81.2% of patients with HS + CCL. Conclusions: The presence of CCL does not influence the clinical and pathologic profile of patients with hippocampal atrophy. Clinical histories and postsurgical outcomes were similar to those of patients with classic HS, suggesting that the CCL is probably, in this set of patients, a coincidental pathology and does not have a role in epileptogenesis.–1491

Intracellular filamentous inclusions containing abnormally phosphorylated tau protein are hallmarks of several human neurodegenerative disorders. This study reveals tau-positive cytoskeletal abnormalities in neurons and glial cells of aged baboons. The brains of four baboons (Papio hamadryas, 20-30 yr of age) were examined using the Gallyas silver technique for neurofibrillary changes and phosphorylation-dependent anti-tau antibodies (AT8, AT100, AT270, PHF-1, TG-3). Conspicuous changes were noted in two animals, 26 and 30 yr of age. In both animals, a combination of neuronal and glial cytoskeletal pathology was seen preferentially affecting limbic brain areas, including the hippocampal formation. In the 30-yr-old animal, numerous tau-positive inclusions were seen in the granule cells of the fascia dentata. These cells even exhibited an accumulation of argyrophilic neurofibrillary tangles. The glial changes affected both astrocytes and oligodendrocytes. Tau-positive astrocytes were seen in perivascular, subpial, and subependymal locations. Tau-positive oligodendrocytes preferentially occurred in limbic fiber tracts including the entorhinal perforant path. Ultrastructurally, tau-positive straight filaments (10-14 nm) in both neurons and glial cells were revealed by anti-tau immunoelectron microscopy. This study thus indicates the potential usefulness of aged baboons for experimental investigation of neuronal and glial filamentous tau pathology. This nonhuman primate species may provide valuable information pertinent to the broad spectrum of human tauopathies.

Entorhinal cortex (EC), fascia dentata (FD), hippocampus (HP), and basal ganglia (BG) were studied in Rett syndrome (RS) cases and compared with control brains and an autism case. Kluver–Barrera and Golgi methods were used. In RS most of the areas of EC, HP, and FD showed severe cell hypochromia. In the EC all cells of layer II and most in layer III were in a state of total chromatolysis or were “ghost” cells, but the cells of layers V and VI were preserved and moderately hyperchromic. In FD and HP the majority of the granular cells and cells of CA3 and CA4 fields were severely hypochromic, whereas in the CA1 field most cells were normal or slightly hypercaryochromic. In BG mostly mild or moderate aberration from normal cell structure was observed: in striatum, mild hypercaryochromia of small neurons and more expressive hyperchromia of large neurons were found; and in pallidum, mild or moderate hypercaryochromia to severe hyperchromia in pallidum internum was found. Degeneration of thick myelinated fibers was evident in pallidum. Large striatal and pallidal neurons showed signs of constructive changes in Golgi slices. These data allow the determination of the cause of the main symptoms of RS. The motor disorders, including specific stereotyped movements, could be related to the enhanced activity of BG cells due to their deafferentation from the side of the neocortex and to supposed hyperactivity of the EC–striatal pathway; the mental retardation and epileptic seizures could be due to FD–HP involvement.

There is considerable controversy whether aberrant fascia dentata (FD) mossy fiber sprouting is an epiphenomena related to neuronal loss or a pathologic abnormality responsible for spontaneous limbic seizures. If mossy fiber sprouting contributes to seizures, then reorganized axon circuits should alter postsynaptic glutamate receptor properties. In the pilocarpine-status rat model, this study determined if changes in alpha amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) and n-methyl-D-aspartic acid (NMDA) receptor subunit mRNA levels correlated with mossy fiber sprouting. Sprague-Dawley rats were injected with pilocarpine (320 mg/kg; i.p.) and maintained in status epilepticus for 6 to 8 hours (pilocarpine-status). Rats were killed during the: (1) latent phase after neuronal loss but before spontaneous limbic seizures (day 11 poststatus; n = 7); (2) early seizure phase after their first seizures (day 25; n = 7); and (3) chronic seizure phase after many seizures (day 85; n = 9). Hippocampi were studied for neuron counts, inner molecular layer (IML) neo-Timm's staining, and GluR1–3 and NMDAR1–2b mRNA levels. Compared with controls, pilocarpine-status rats in the: (1) latent phase showed increased FD GluR3, NMDAR1, and NMDAR2b; greater CA4 and CA1 NMDAR1; and decreased subiculum GluR1 hybridization densities; (2) early seizure phase showed increased FD GluR3, increased CA1 NMDAR1, and decreased subiculum NMDAR2b densities; and (3) chronic seizure phase showed increased FD GluR2; increased FD and CA4 GluR3; decreased CA1 GluR2; and decreased subiculum GluR1, GluR2, NMDAR1, and NMDAR2b levels. In multivariate analyses, greater IML neo-Timm's staining: (1) positively correlated with FD GluR3 and NMDAR1 and (2) negatively correlated with CA1 and subiculum GluR1 and GluR2 mRNA levels. These results indicate that: (1) hippocampal AMPA and NMDA receptor subunit mRNA levels changed as rats progressed from the latent to chronic seizure phase and (2) certain subunit alterations correlated with mossy fiber sprouting. Our findings support the hypothesis that aberrant axon circuitry alters postsynaptic hippocampal glutamate receptor subunit stoichiometry; this may contribute to limbic epileptogenesis. J. Neurosci. Res. 54:734–753, 1998. © 1998 Wiley-Liss, Inc.

This study determined whether hippocampal kainate (KA) receptor mRNA levels were increased or decreased in temporal lobe epilepsy patients compared with nonseizure autopsies. Hippocampal sclerosis (HS; n = 17), nonsclerosis (non-HS; n = 11), and autopsy hippocampi (n = 9) were studied for KA1-2 and GluR5-7 mRNA levels using semiquantitative in situ hybridization techniques, along with neuron densities. Compared with autopsy hippocampi, HS and non-HS cases showed decreased GluR5 and GluR6 hybridization densities per CA2 and/or CA3 pyramid. Furthermore, HS patients demonstrated increased KA2 and GluR5 hybridization densities per granule cell compared with autopsy hippocampi. These findings indicate that chronic temporal lobe seizures were associated with differential changes in hippocampal KA1-2 and GluR5-7 hybridization densities that vary by subfield and pathology group. In temporal lobe epilepsy patients, these results support the hypothesis that pyramidal cell GluR5 and GluR6 mRNA levels are decreased as a consequence of seizures, and in HS patients granule cell KA2 and GluR5 mRNA levels are increased in association with aberrant fascia dentata mossy fiber sprouting and/or hippocampal neuronal loss.

This study compared temporal lobe epilepsy patients, along with kindled animals and self sustained limbic status epilepticus (SSLSE) rats for parallels in hippocampal AMPA and NMDA receptor subunit expression. Hippocampal sclerosis patients (HS), non-HS cases, and autopsies were studied for: hippocampal AMPA GluR1-3 and NMDAR12b mRNA levels using in situ hybridization: GluR1, GluR2/3, NMDAR1, and NMDAR2(ab) immunoreactivity (IR); and neuron densities. Similarly, spontaneously seizing rats after SSLSE, kindled rats, and control animals were studied for: fascia dentata neuron densities: GluR1 and NMDAR2(ab) IR; and neo-Timm's staining. In HS and non-HS cases, the mRNA hybridization densities per granule cell, as well as molecular layer IR, showed increased GluR1 (relative to GluR2/3) and increased NMDAR2b (relative to NMDAR1) compared to autopsies. Likewise, the molecular layer of SSLSE rats with spontaneous seizures demonstrated more neo-Timm's staining, and higher levels of GluR1 and NMDAR2(ab) IR compared to kindled animals and controls. These results indicate that hippocampal AMPA and NMDA receptor subunit mRNAs and their proteins are differentially increased in association with spontaneous, but not kindled, seizures. Furthermore, there appears to be parallels in fascia dentata AMPA and NMDA receptor subunit expression between HS (and non-HS) epileptic patients and SSLSE rats. This finding supports the hypothesis that spontaneous seizures in humans and SSLSE rats involve differential alterations in hippocampal ionotrophic glutamate receptor subunits. Moreover, non-HS hippocampi were more like HS cases than hippocampi from kindled animals with respect to glutamate receptors; therefore, hippocampi from kindled rats do not accurately model human non-HS cases, despite some similarities in neuron densities and mossy fiber axon sprouting.

Patterns of neuronal activity recorded in CA1 of the hippocampus and in neocortex during waking-behavior, are reactivated during subsequent slow-wave sleep (SWS). It has been suggested that this reactivation may originate in the hippocampal CA3 region, where modifiable excitatory recurrent connections are abundant and where sharp-waves, in which the reactivation is most robust, appear to arise. The present experiment investigated whether ensemble firing patterns of granule cells in the fascia dentata (FD), an area ‘upstream’ from CA3, are also reactivated during sleep. Populations of FD granule cells were recorded from during spatial behavior and during prior and subsequent SWS. Firing rate correlations between cell-pairs with overlapping place fields were significantly enhanced during post behavioral sleep compared to pre behavioral sleep. Correlations between cells with non-overlapping place fields or which were silent during maze behavior, were not changed. Thus, reactivation of experience-specific correlation states also occurs in granule cells during sleep. Because these cells do not have excitatory interconnections, but form a major input to CA3 pyramidal cells, current models predicted that sleep reactivation would appear first in CA3. There are, however, both extensive polysynaptic excitatory interactions among granule cells and feedback from CA3 pyramidal cells. Granule cells also receive indirect input from neocortical regions known to undergo trace reactivation. Although a simple model for a CA3 origin of the reactivation phenomenon cannot be confirmed, the present results extend our understanding of the generality of this phenomenon.

The present study aimed to assess the developmental progress of the hippocampal nitric oxide (NO) system within adulthood by comparing the density of NO-producing neurons in the fascia dentata and Ammon's horn in two groups of adult male rats using NADPH-diaphorase (NADPH-d) histochemistry. One group comprised 6-month-old rats (early adulthood), and the other 12-month-old rats (middle-adulthood). Areal density (number of neurons per unit area) of NADPH-d positive neurons along the three hippocampal axes (septo-temporal, transverse and radial axes) were subjected to quantitative analyses. There were significant variations in the density of NADPH-d-reactive neurons along the transverse and radial axes of the hippocampus, similar to what have been described previously. Comparison between 6-month and 12-month-old rats indicated a substantial reduction in the density of NADPH-d-reactive neurons in the fascia dentata (69%) and Ammon's horn (54%) of the latter group. This reduction was relatively uniform along the septotemporal and radial axes, but appeared to be more pronounced in the fascia dentata and in the proximal region of Ammon's horn. Our finding showed that the hippocampal NO system can undergo significant changes within adulthood. It further highlighted the possibility that an age-related reduction in the capacity to produce NO may not be directly responsible for the cognitive decline associated with senescence, but rather predisposes neuronal degeneration in later life.

Rhythmic spontaneous bursting is a fundamental hallmark of the immature hippocampal activity recorded in vitro. These bursts or giant depolarizing potentials (GDPs) are GABA- and glutamatergic-driven events. The mechanisms of GDPs generation are still controversial, since although a hilar origin has been suggested, GDPs were also recorded from isolated CA3 area. Here, we have investigated the origin of GDPs in hippocampal slices from newborn rabbits. Simultaneous intracellular recordings were performed in CA3, CA1 and the fascia dentata. We found a high degree of correlation between the spontaneous GDPs present in CA3 and CA1 regions. Cross-correlation analysis demonstrated that CA3 firing precedes CA1 by about 192 ms, although a significant population of discharges was recorded first in CA1 (20%). Granule cells (GCs) in the fascia dentata also showed GDPs. The frequency of these events (1.46 +/- 1.25 GDPs/min, n = 7) is significantly lower when compared with that from CA3 (3.13 +/- 1.43 GDPs/min, n = 10) or CA1 (2.94 +/- 1.36 GDPs/min, n = 17). Dual recordings from CA3 and fascia dentata cells showed synchronous bursts in both regions with no prevalent preceding area. By recording from isolated areas we found that CA1, CA3 and the fascia dentata can produce GDPs, suggesting that they emerge as a property of local circuits present throughout the hippocampus.

The rat fascia dentata is frequently used as a model system to analyze normal as well as pathological processes of the brain. The normal anatomy of the fascia dentata is the basis for a meaningful interpretation of experimentally induced changes in this brain region. Using anterograde tracing with Phaseolus vulgaris-leucoagglutinin (PHAL) previously unknown commissural as well as entorhinal fiber systems to the fascia dentata were described. These fiber systems need to be incorporated into current concepts of the hippocampal network since they have profound implications for studies of lesion effects in this brain region.

The medial cortex of lizards is a three-layered brain region displaying cyto- and chemoarchitectonical, connectional, and ontogenetic characteristics that relate it to the hippocampal fascia dentata of mammals. Three interneuron types located in the cell layer and ten others in the inner plexiform layer (six in the juxtasomatic zone and four in the deep zone) are described in this study. The granuloid neurons, web-axon neurons, and deep-fusiform neurons lay within the cell layer. These neurons were scarce; they were probably gamma-aminobutyric acid (GABA)-, and parvalbumin-immunoreactive and presumably participated in feed forward as well as in feed back inhibition of the principal projection cells of the lizard medial cortex. In the juxtasomatic inner plexiform layer, the smooth vertical neurons, smooth horizontal neurons, small radial neurons, large radial neurons, pyramidal-like radial neurons, and spheroidal neurons were found. They were all probably GABA-, and parvalbumin-immunoreactive and were involved in feed forward inhibition of principal medial cortex cells. In the deep inner plexiform layer lay the giant-multipolar neurons, long-spined polymorphic neurons, periventricular neurons, and alveus-horizontal neurons. These neurons were probably GABA-immunoreactive and either neuropeptide- (somatostatin-neuropeptide Y) or parvalbumin-immunoreactive. They seemed to be involved in feed back or even occasionally in feed forward inhibition phenomena.

The medial cortex of lizards is a simple three-layered brain region displaying many characteristics that parallel the hippocampal fascia dentata of mammals. Its principal neurons form a morphologically diverse population, partly as a result of the prominent continuous growth of this nervous center. By using the classic Golgi impregnation method, we describe here the morphology of the principal neurons populating the medial cortex of Podarcis hispanica. These were projection neurons giving off descending axons. These axons displayed deep collateral branches provided with prominent axonal boutons, while the main axonal branch reached adjacent cortical areas and the bilateral septum. According to three main classification criteria, dendritic tree pattern, dendritic spine covering, and soma size, we have distinguished eight different types of projection neurons. Five of them, "heavily spiny granular" (monotufted, medium-sized), "heavily spiny bitufted" (large), "spiny bitufted" (medium-sized), "sparsely spiny bitufted" (small), and "superficial multipolar" (small), were found in the cell layer, whereas the three others lay outside this layer and were regarded as ectopic types ("outer plexiform ectopic bitufted," "inner plexiform ectopic bitufted", and "inner plexiform monotufted"). Additional secondary criteria, soma position and shape, allowed us to further classify bitufted neurons into three distinct subtypes each: "superficial-round," "intermediate-fusiform," and "deep-pyramidal." Moreover, a variety of small impregnated cells were observed; they probably represented newly generated immature neurons that had not yet completed their development. These cell types were compared with those reported previously in Golgi, immunocytochemical, and electron-microscopy studies, both in the reptilian medial cortex and in the mammalian dentate area. Presumably age-related changes and synaptic relationships of these projection cells in the medial cortex circuitry were analyzed.

The most frequently used model of neonatal cerebral hypoxia–ischemia consists of a 7-day postnatal rat model with combined common carotid artery ligation and hypoxemia. Neuropathologic studies have shown major differences between this 7-day postnatal rat model and a similar adult model in regard to overall cerebral vulnerability, type and distribution of lesions. It is not clear how and when during animals' development these changes in cerebral vulnerability take place. To determine this we studied groups of rats of 2 to 30 postnatal days. The animals underwent unilateral common carotid artery ligation followed by breathing in 8% oxygen for 30, 60, 90, or 120 min and their brains were examined at 24- or 72-h recovery intervals. Due to resistance of 2–3-day-old rats to develop cerebral hypoxic–ischemic damage, 5% O2 was used instead of 8% O2. The results indicate that: (i) There is an overall increase in severity of cerebral lesions on the side of common carotid artery ligation between 2 and 7 postnatal days. There is also an increase in the frequency of cerebral lesions in developing animals with increasing age. (ii) Hippocampus is remarkably resistant to hypoxic–ischemic insult at 2–3 postnatal days but becomes progressively vulnerable, and by age 13 postnatal days hippocampal vulnerability far exceeds that of cortex. (iii) Cortical lesions change from predominantly columnar cell death to laminar selective neuronal death at age 13 postnatal days. (iv) Also significant changes occur in relative vulnerability of various hippocampal regions during development. During the first 5 postnatal days relative vulnerability of hippocampal regions is similar, but as the animals' development proceeds and hippocampal vulnerability increases lesions tend to involve specific regions while sparing others. By age 13 postnatal days CA1 and lateral CA3 develop increased vulnerability while medial CA3 and fascia dentata become relatively resistant and by 21 postnatal days adult pattern of CA1 selective vulnerability is approached. The underlying mechanisms for these changes in regional vulnerability to cerebral hypoxia-ischemia during development should be sought in complex regional anatomic, functional, and metabolic alterations that take place as brain matures.

Mice lacking prion protein (PrP-null) are resistant to transmissible spongiform encephalopathies. However, the normal functions of this highly conserved protein remain controversial. This study examines whether PrP-null mice develop normal neuronal pathways, specifically the mossy fibre pathway, within the hippocampus. Timm stained hippocampal sections from the PrP-null group had more granules than the controls in: the granule cell layer, the inner molecular layer of the dentate gyrus, and the infrapyramidal region of CA3. This resembles the mossy fibre collateral and terminal sprouting seen in certain epilepsies. The abnormal connectivity might be predicted to promote epileptiform activity, but extracellular electrophysiological recordings from the granule cell layer revealed a reduced excitability in the PrP-null group, both with and without blockade of GABAA receptor-mediated inhibition. We propose that reorganization of neuronal circuity is a feature of PrP-null mice.

In order to observe changes owing to aging and Alzheimer's disease (AD) in the volumes of subdivisions of the hippocampus and the number of neurons of the hippocampal formation, 18 normal brains from subjects who died of nonneurological causes and had no history of long-term illness or dementia (ten of these brains comprised the aged control group) and 13 AD brains were analyzed. An optimized design for sampling, measuring volume by using the Cavalieri principle, and counting the number of neurons by using the optical disector was implemented on 50 microns-thick cresyl-violet sections. The mean total volume of the principal subdivisions of the hippocampal formation (fascia dentata, hilus, CA3-2, CA1, and subiculum) showed a negative correlation with age in normal subjects (r = -0.56, 2P < 0.05), and a 32% mean reduction in the AD group compared with controls (P < 0.001). This finding supports the measurement of the coronal cross-sectional area and the volume of the hippocampal formation in the clinical diagnosis of AD. There was an inverse relationship between the age of normal subjects and the number of neurons in CA1 (r = -0.84, 2P < 0.0001) and subiculum (r = -0.49, 2P < 0.05) but not in other subdivisions. Pronounced AD-related reductions in neuron number were found only in the subiculum and the fascia dentata. Compared with controls, both losses represented 23% of neurons (P < 0.05). These results 1) confirm that AD is a qualitatively different process from normal aging and 2) reveal the regional selectivity of neuron loss within the hippocampal formation in aging and AD, which may be relevant to understanding the mechanisms involved in the neuron loss associated with the two processes.

This study determined whether there were differences in hippocampal neuron loss and synaptic plasticity by comparing rats with spontaneous epilepsy after limbic status epilepticus and animals with a similar frequency of kindled seizures. At the University of Virginia, Sprague-Dawley rats were implanted with bilateral ventral hippocampal electrodes and treated as follows; no stimulation (electrode controls; n=5): hippocampal stimulation without status (stimulation controls; n=5); and limbic status from continuous hippocampal stimulation (n=12). The limbic status group were electrographically monitored for a minimum of four weeks. Four rats had no recorded chronic seizures (status controls), and all three control groups showed no differences in hippocampal pathology and were therefore incorporated into a single group (controls). Eight limbic status animals eventually developed chronic epilepsy (spontaneous seizures) and an additional eight rats were kindled to a similar number and frequency of stage 5 seizures (kindled) as the spontaneous seizures group. At the University of California (UCLA) the hippocampi were processed for: (i) Niss1 stain for densitometric neuron counts; (ii) neo-Timm's histochemistry for mossy fiber sprouting; and (iii) immunocytochemical staining for glutamate decarboxylase, N-methyl-D-aspartate receptor subunit 2, AMPA receptor subunit 1 and the GABA(A) receptor. In the fascia dentata inner and outer molecular layers the neo-Timm's stain and immunoreactivity was quantified as gray values using computer image analysis techniques. Statistically significant results (P

Background Aging is typically accompanied by memory decline and changes in hippocampal function. Among these changes is a decline in the activity of the dentate gyrus (DG) during behavior. Lasting memory, however, is thought to also require recapitulation of recent memory traces during subsequent rest – a phenomenon, termed memory trace reactivation, which is compromised in hippocampal CA1 with progressive age. This process has yet to be assessed in the aged DG, despite its prominent role in age-related memory impairment. Using zif268 transcription to measure granule cell recruitment, DG activity in adult and aged animals was assessed both during spatial exploration and as animals remained at rest in the home cage in order to detect potential memory-related replay. Results Consistent with the observation of memory trace reactivation in DG, the probability that an individual granule cell transcribes zif268 during rest in the animal’s home cage is increased by recent experience in a novel environment. Surprisingly, a comparable increase was observed in the probability of granule cells in the aged DG expressing zif268 during rest. Moreover, no significant age-related difference was observed in the number of granule cells expressing zif268 during rest. Thus, the number and pattern of granule cell expression of zif268 during rest is preserved in aged animals, despite a significant decline in exploration-related zif268 expression. Conclusions These data lead to the hypothesis that the input the aged DG receives from backprojections from CA3 (the region widely hypothesized to mediate reactivation) remains functionally intact despite loss of innervation from the perforant path.

Scientific studies addressing anatomical variations in meditators’ brains have emerged rapidly over the last few years, where significant links are most frequently reported with respect to gray matter (GM). To advance prior work, this study examined GM characteristics in a large sample of 100 subjects (50 meditators, 50 controls), where meditators have been practicing close to twenty years, on average. A standard, whole-brain voxel-based morphometry approach was applied and revealed significant meditation effects in the vicinity of the hippocampus, showing more GM in meditators than in controls as well as positive correlations with the number of years practiced. However, the hippocampal complex is regionally segregated by architecture, connectivity, and functional relevance. Thus, to establish differential effects within the hippocampal formation (cornu ammonis, fascia dentate, entorhinal cortex, subiculum) as well as the hippocampal-amygdaloid transition area, we utilized refined cytoarchitectonic probabilistic maps of (peri-) hippocampal subsections. Significant meditation effects were observed within the subiculum specifically. Since the subiculum is known to play a key role in stress regulation and meditation is an established form of stress reduction, these GM findings may reflect neuronal preservation in long-term meditators – perhaps due to an attenuated release of stress hormones and decreased neurotoxicity.

Entorhinal fibers to the fascia dentata originating from layer II stellate neurons are known to terminate exclusively in the outer two thirds of the molecular layer, where they innervate distal dendritic portions of dentate neurons. Using anterograde tracing withPhaseolus vulgarisleucoagglutinin, we unraveled a previously unknown entorhinal projection that directly innervates proximal dendritic portions and somata of granule cells and GABAergic neurons. This projection originates from neurons located in entorhinal layers IV–VI of the medial entorhinal area. These fibers enter the outer two thirds of the molecular layer, traverse the inner molecular layer (IML) and granule cell layer, where they form numerous boutons, and finally arborize subjacent to the granule cells. Correlated light and electron microscopy revealed that the boutons formed by these fibers establish asymmetric synapses on dendrites in the IML, on spines and somata of granule cells, and on spineless dendrites subjacent to the granule cell layer. Postembedding immunogold staining indicates that this entorhino-dentate projection is not GABAergic and that it also terminates on GABAergic inhibitory neurons. These data demonstrate that not all entorhino-dentate fibers display a similar high laminar specificity for the outer molecular layer (OML). Although fibers from the superficial layers of the entorhinal cortex terminate exclusively in the OML, entorhinal fibers arising from deeper layers are not confined to laminar boundaries. Finally, the possibility that these supposedly excitatory entorhinal afferents may monosynaptically activate proximal dendrites and somata of dentate neurons needs to be incorporated into contemporary concepts of the hippocampal network.

Summary: Neuronal cell distributions were measured for anterior and posterior locations in the hippocampi of epilepsy patients who were seizure-free after temporal lobectomy. Patients were divided into two groups, those with an early risk factor, defined as a neurologic insult occurring in the first 4 years of life, and those with no early risk factor. Early-risk patients had lower hilar cell densities, lower granule cell densities, and fewer granule cells per millimeter, a measure related to total granule cell number, than no early risk patients. Moreover, each risk group had different anteroposterior density gradients for granule cells and hilar cells. These differences in cell distribution may arise from different patterns of cell loss or cell migration in the dentate gyrus during development. In the early-risk group, there was also a distinction between patients with a history of febrile convulsions without CNS infection and patients with a history of meningitis or encephalitis. These two subgroups had similar numbers of granule cells. However, the meningitis/encephalitis subgroup exhibited a wider granule cell layer, suggesting that the granule cell layer was more dispersed. Our results support the hypothesis of a predominantly anterior hippocampal insult in temporal lobe epilepsy (TLE). In nonepileptic hippocampus, the ratio of putatively excitatory granule neurons to putatively inhibitory hilar neurons is highest in the anterior hippocampus. This ratio may explain in part why the anterior hippocampus is more prone to cell loss and seizures.

The present study addresses whether seizures, which result from the chronic block of inhibition caused by an intrahippocampal injection of tetanus toxin, induce axonal sprouting of the hippocampal mossy fibres. Timm stain was used to identify the mossy fibre terminals. In nine of 15 animals killed at 1 month or later after an injection of tetanus toxin, Timm-stained terminals were observed bilaterally in the inner molecular layer and in seven animals a meshwork of Timm-stained fibres/ terminals was also observed bilaterally in the outer molecular layer of the fascia dentata. None of these changes were observed in any of the 12 saline-injected controls. There was no obvious correlation between the number of motor fits an animal exhibited and the amount of Timm-stained fibre sprouting present in either the inner or outer molecular layer. The Timm-stained axonal sprouting into the outer molecular layer of the fascia dentata may simply reflect the reinnervation of sites on the granule cell dendrites, previously occupied by the terminals of the hilar somatostatin-containing cells. These hilar somatostatin-containing cells which are believed to project to the outer molecular layer are known to succumb to the seizure activity in this animal model of epilepsy.

Summary In this study, we determined whether childhood seizures were associated with hippocampal neuron loss and mossy fibre synaptic reorganization and if hippocampal sclerosis evolved from longer seizure histories. Children undergoing surgical treatment for catastrophic epilepsy were grouped into the following pathology categories: (i) those with generalized seizures and extra-hippocampal congenital pathologies (i.e. prenatal cortical dysplasia; n = 17); (ii) cases of generalized seizures and extra-hippocampal acquired lesions (i.e. postnatal ischaemic injuries and encephalitis: n = 7); (iii) children with complex partial hippocampal epilepsy (n=4). Further, to determine whether the epileptogenic location influenced hippocampal pathology, the seizure focus was classified as (i) hippocampal, (ii) temporal (n = 13) or (iii) extra-temporal (n = 11). Surgical and autopsy (n = 23) hippocampi were studied for (i) fascia dentata (FD) and Ammon's horn (AH) neuron densities: (ii) thickness, height or length of the FD molecular layer, stratum granulosum (SG) and stratum pyramidale: and (iii) grey value (GV) densities of supragranular neo-Timm's staining. Statistically significant results (P

Exchange of nerve connections between developing neural grafts and adult recipient brains is enhanced for grafts placed in excitotoxic lesions, which spare recipient brain afferent axons in otherwise neuron-depleted lesion areas. In previous studies of hippocampal grafts placed in such lesions, we have used anterograde axonal degeneration, histochemical Timm staining and acetylcholinesterase to demonstrate host-graft interconnectivity. In this study, we have now used three anterograde axonal tracers, Phaseoulus vulgaris-leukoaglutinin (PHA-L), biocytin and biotinylated dextran amine (BDA), which allow individual fibers to be traced. Adult male rats with 1-week-old axon-sparing ibotenic acid lesions of the dorsal CA3 region or fascia dentata were grafted into the respective lesions with suspensions of fetal (El8-19) CA3 cells or a block of neonatal fascia dentata tissue. One to twelve months later, recipients were injected with Phaseoulus vulgaris-leukoaglutinin or biocytin in the hippocampus contralateral to the graft to trace the possible ingrowth and distribution within the transplants of host commissural axons, or into the transplants with biotinylated dextran amine in order to trace outgrowing graft fibers. In rats with succesfull host Phaseoulus vulgaris-leukoaglutinin or biocytin injections, the CA3 and fascia dentata transplants were innervated by labelled host commissural fibers. In the dentate transplants, most commissural fibers projected as normally to the inner part of the molecular layer, with fewer aberrant fibers extending more superficially into the molecular layer. Following injections into the fascia dentata and CA3 grafts of biotinylated dextran amine, labelled graft fibers were traced into the ipsilateral host dentate hilus, CA3 and CA1. From some CA3 containing grafts, a few labelled fibers were also observed passing through the host fimbria-fornix to the lateral septum on the grafted side. A few fibers were projected as far as to the most septal levels of the contralateral CA1.

The distribution of neuropeptide Y immunoreactive (NPY-ir) neurons in organotypic cultures of hippocampi from neonates was compared to that seen in adult rats. In addition to the known NPY-ir neurons in the hippocampus proper and in the hilus of the fascia dentata, isolated, large, multipolar, NPY-ir neurons were observed in the subiculum and in areas CA1 and CA3. Their axons projected into stratum radiatum of the hippocampus proper and into the molecular layers and hilus of the fascia dentata where they branched profusely. These NPY-ir neurons were regularly distributed throughout the septo temporal extent of the hippocampus and were present in both neonates and adult hippocampi. The hilar NPY-ir neurons have always been considered the source of the NPY-ir plexus in the outer molecular layer of the dentate gyrus. However, our results show that there is also a contribution from the NPY-ir neurons in the hippocampus proper.

O'Keefe and Recce [1993] Hippocampus 3:317-330 described an interaction between the hippocampal theta rhythm and the spatial firing of pyramidal cells in the CA1 region of the rat hippocampus: they found that a cell's spike activity advances to earlier phases of the theta cycle as the rat passes through the cell's place field. The present study makes use of large-scale parallel recordings to clarify and extend this finding in several ways: 1) Most CA1 pyramidal cells show maximal activity at the same phase of the theta cycle. Although individual units exhibit deeper modulation, the depth of modulation of CA1 population activity is about 50%. The peak firing of inhibitory interneurons in CA1 occurs about 60 degrees in advance of the peak firing of pyramidal cells, but different interneurons vary widely in their peak phases. 2) The first spikes, as the rat enters a pyramidal cell's place field, come 90 degrees-120 degrees after the phase of maximal pyramidal cell population activity, near the phase where inhibition is least. 3) The phase advance is typically an accelerating, rather than linear, function of position within the place field. 4) These phenomena occur both on linear tracks and in two-dimensional environments where locomotion is not constrained to specific paths. 5) In two-dimensional environments, place-related firing is more spatially specific during the early part of the theta cycle than during the late part. This is also true, to a lesser extent, on a linear track. Thus, spatial selectivity waxes and wanes over the theta cycle. 6) Granule cells of the fascia dentata are also modulated by theta. The depth of modulation for the granule cell population approaches 100%, and the peak activity of the granule cell population comes about 90 degrees earlier in the theta cycle than the peak firing of CA1 pyramidal cells. 7) Granule cells, like pyramidal cells, show robust phase precession. 8) Cross-correlation analysis shows that portions of the temporal sequence of CA1 pyramidal cell place fields are replicated repeatedly within individual theta cycles, in highly compressed form. The compression ratio can be as much as 10:1. These findings indicate that phase precession is a very robust effect, distributed across the entire hippocampal population, and that it is likely to be inherited from the fascia dentata or an earlier stage in the hippocampal circuit, rather than generated intrinsically within CA1. It is hypothesized that the compression of temporal sequences of place fields within individual theta cycles permits the use of long-term potentiation for learning of sequential structure, thereby giving a temporal dimension to hippocampal memory traces.

The calcium-binding protein calretinin is present in an intrinsic GABAergic and an extrinsic non-GABAergic system in the rat and monkey hippocampal formation. Important species differences have been noted in hippocampal cell types immunostained for calretinin and the termination pattern of calretinin containing hypothalamic afferents in the hippocampus. In the present study, calretinin-containing neurons were visualized using immunocytochemistry in the human hippocampal formation of individuals which showed no significant neuropathological alterations. Calretinin-immunoreactivity was present exclusively in non-granule cells of the dentate gyrus and in non-pyramidal cells of Ammon's horn. Calretinin-positive neurons were found most frequently in the hilus of the fascia dentata and in strata radiatum and lacunosum-moleculare of CA1, whereas neurons in CA2 and CA3 were rarely immunostained. The majority of calretinin-immunoreactive neurons were small, bipolar or fusiform neurons. The dendritic trees of the calretinin-positive neurons were, for the most part, parallel to the dendrites of the principal cells. In the hilus, however, we observed cells with dendrites restricted to the hilar area. These dendrites were parallel to the granule cell layer. In the stratum lacunosum-moleculare, neurons with dendrites oriented parallel to the hippocampal fissure were frequently detected. In general, dendrites were smooth or sparsely spiny, displaying small conventional spines. The axons usually emerged from the proximal dendrite and could be followed over long distances. Axons were thin, had small varicosities and displayed only few collaterals which branched relatively far away from the cell body. Distinct bands of darkly stained calretinin-positive fibers occupied the innermost portion of the dentate molecular layer and the pyramidal cell layer of CA2. This distribution of calretinin-immunoreactive structures in the human hippocampus is similar to that observed in other primates but differs from that described in lower mammals, i.e., the rat. Our findings suggest that primates may share a common hippocampal calretinin-containing system, presumably both the intrinsic GABAergic and the extrinsic hypothalamic non-GABAergic components.

Kindling is an animal model of epilepsy which is accompanied by morphological and biochemical changes in the brain, including sprouting of fibers and increased transmitter release. Here we have examined the immunocytochemical expression of 1) GAP-43, a growth-associated protein, which is a neuron-specific PKC substrate, particularly expressed in development and regeneration and 2) glial fibrillary acidic protein (GFAP), part of the astrocytic cytoskeleton, after perforant path kindling. Subsequent to kindling, GAP-43 immunoreactivity was increased in CA1 stratum lacunosum-moleculare and the inner and outer molecular layer of the fascia dentata. Other hippocampal subregions showed a lower increase. GFAP immunoreactivity was increased in the entire hippocampus, but especially in stratum lacunosum-moleculare of the CA1 and the hilus of fascia dentata. The difference between the number of GFAP-positive profiles in the hippocampus of control rats and in fully kindled rats was found to be non-significant. We interpret these findings as being related to both plastic neuronal changes and possible neuronal degeneration.

This study determined differences of fascia dentata (FD) peptide and inhibitory neuroanatomy between patients with epileptogenic hippocampal sclerosis (HS), those with extrahippocampal seizure pathologies, and autopsy comparisons. Surgically treated temporal lobe epilepsy patients were clinically classified into two pathogenic categories: (1) HS with focal mesial temporal neuroimaging and histories of initial precipitating injuries to the brain (n = 18) and (2) non-HS patients with extrahippocampal mass lesions or idiopathic seizures (i.e., without lesions or HS; mass lesion/idiopathic; n = 9). The hippocampal sections were studied for (1) granule cell, hilar, CA4, and CA3 neuron densities; (2) hilar densities and the percentage of neurons immunoreactive (IR) for neuropeptide Y (NPY), somatostatin (SS), and glutamate decarboxylase (GAD); (3) densities of GAD neurons in the lower granule cell and infragranular zone (basket-like cells); (4) the semiquantitative pattern of IR peptides/GAD FD molecular layer axon sprouting; (5) IR gray values (GV) of the FD molecular layers; and (6) the thickness of the supragranular molecular layer. Results showed the following. (1) Compared to autopsies, both HS and mass lesion/idiopathic patients showed less granule cell and CA3 neuron densities, but there were no statistical differences between the latter two pathogenic categories. (2) By contrast, compared to autopsies and mass lesion/idiopathic cases, HS patients showed less hilar and CA4 neuron densities, and there were no differences between autopsies and mass lesion/idiopathic. (3) Compared to autopsies, the NPY and SS hilar neuron densities in HS patients, but not mass lesion/idiopathic cases, were less. (4) Compared to autopsies, the hilar GAD neuron densities for HS and mass lesion/idiopathic patients were not less. (5) In HS patients the averaged percentages of hilar SS neurons were less than autopsies, and no other differences of IR hilar percentages were found. (6) The densities of GAD basket-like neurons and the thickness of the supragranular molecular layer were not different between any combination of pathogenic categories and autopsies. (7) By semiquantitative visual assessments, peptides/GAD axon sprouting into the FD was greater in HS compared to mass lesion/idiopathic or autopsies. (8) Compared to mass lesion/idiopathic cases, in HS NPY outer molecular layer GVs were lower, SS GVs were not different, and GAD inner molecular layer GVs were higher. (9) Analyses comparing the two pathogenic categories and neuron densities with peptides/GAD axon sprouting found six comparisons that correlated sprouting with hilar and CA4 neuron losses, and four comparisons showing greater sprouting in HS compared to mass lesion/idiopathic.(ABSTRACT TRUNCATED AT 400 WORDS)