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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.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked gene MECP2. Girls with RTT show dramatic changes in brain function, but relatively few studies have explored the structure of neural circuits. Examining two mouse models of RTT (Mecp2B and Mecp2J), we previously documented changes in brain anatomy. Herein, we use confocal microscopy to study the effects of MeCP2 deficiency on the morphology of dendrites and axons in the fascia dentata (FD), CA1 area of hippocampus, and motor cortex following Lucifer yellow microinjection or carbocyanine dye tracing. At 3 weeks of age, most (33 of 41) morphological parameters were significantly altered in Mecp2B mice; fewer (23 of 39) were abnormal in Mecp2J mice. There were striking changes in the density and size of the dendritic spines and density and orientation of axons. In Mecp2B mice, dendritic spine density was decreased in the FD (approximately 11%), CA1 (14-22%), and motor cortex (approximately 16%). A decreased spine head size (approximately 9%) and an increased spine neck length (approximately 12%) were found in Mecp2B FD. In addition, axons in the motor cortex were disorganized. In Mecp2J mice, spine density was significantly decreased in CA1 (14-26%). In both models, dendritic swelling and elongated spine necks were seen in all areas studied. Marked variation in the type and extent of changes was noted in dendrites of adjacent neurons. Electron microscopy confirmed abnormalities in dendrites and axons and showed abnormal mitochondria. Our findings document widespread abnormalities of dendrites and axons that recapitulate those seen in RTT.

– 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 chondroitin sulfate proteoglycan NG2 is a component of the glial scar following brain injury. Because of its growth inhibiting properties, it has been suggested to impede axonal regeneration. To study whether NG2 could also regulate axonal growth in denervated brain areas, changes in NG2 were studied in the rat fascia dentata following entorhinal deafferentation and were correlated with the post-lesional sprouting response. Laser microdissection was employed to selectively harvest the denervated molecular layer and combined with quantitative RT-PCR to measure changes in NG2 mRNA (6 h, 12 h, 2 days, 4 days, 7 days post-lesion). This revealed increases of NG2 mRNA at day 2 (2.5-fold) and day 4 (2-fold) post-lesion. Immunocytochemistry was used to detect changes in NG2 protein (1 days, 4 days, 7 days, 10 days, 14 days, 30 days, 6 months post-lesion). NG2 staining was increased in the denervated outer molecular layer at day 1 post-lesion, reached a maximum 10 days post-lesion, and returned to control levels thereafter. Electron microscopy revealed NG2 immunoprecipitate on glial surfaces and in the extracellular matrix around neuronal profiles, indicating that NG2 is secreted following denervation. Double labeling of NG2-immunopositive cells with markers for astrocytes, microglia/macrophages, and mature oligodendrocytes suggested that NG2 cells are a distinct glial subpopulation before and after entorhinal deafferentation. BrdU labeling revealed that some of the NG2-positive cells are generated post-lesion. Taken together, our data revealed a layer-specific upregulation of NG2 in the denervated fascia dentata that coincides with the sprouting response. This suggests that NG2 could regulate lesion-induced axonal growth in denervated areas of the brain.

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.

Entorhinal cortex lesion (ECL) partially denervates the fascia dentata of the hippocampus. This is said to induce the sprouting of intact fibers from neighboring layers that invade the zone of the degenerating axons. However, recent studies using anterograde tracing failed to demonstrate sprouting across laminar boundaries. Sprouting does occur, but it mainly involves unlesioned fiber systems terminating within the layer of fiber degeneration. It is now of interest to identify the cues that could underlie this layer-specific sprouting response. Since extracellular matrix (ECM) molecules delineate boundaries of axonal growth during development, it was tested whether these molecules play a similar role during the sprouting process following ECL. After ECL, reactive astrocytes rapidly synthesize and secrete growth-inhibiting ECM molecules, such as tenascin-C and the chondroitin sulfate proteoglycan neurocan, into the ECM of the outer molecular layer. These molecules form a sharp border against the nondenervated inner molecular layer. This pattern of ECM molecule expression may contribute to the layer-specific sprouting response of surviving afferents after ECL: axons trying to grow into the denervated outer molecular layer, for example, from the inner molecular layer, would be deflected by a growth-inhibiting ECM barrier.

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.

Reactive axonal sprouting occurs in the fascia dentata after entorhinal cortex lesion. This sprouting process has been described extensively in the rat, and plasticity-associated molecules have been identified that might be involved in its regulation. To demonstrate causal relationships between these candidate molecules and the axonal reorganization process, it is reasonable to analyze knockout and transgenic animals after entorhinal cortex lesion, and because gene knockouts are primarily generated in mice, it is necessary to characterize the sprouting response after entorhinal cortex lesion in this species. In the present study, Phaseolus vulgaris-leucoagglutinin (PHAL) tracing was used to analyze the commissural projection to the inner molecular layer in mice with longstanding entorhinal lesions. Because the commissural projection to the fascia dentata is neurochemically heterogeneous, PHAL tracing was combined with immunocytochemistry for calretinin, a marker for commissural/associational mossy cell axons. Using both techniques singly as well as in combination (double-immunofluorescence) at the light or electron microscopic level, it could be shown that in response to entorhinal lesion mossy cell axons leave the main commissural fiber plexus, invade the denervated middle molecular layer, and form asymmetric synapses within the denervated zone. Thus, the commissural sprouting response in mice has a considerable translaminar component. This is in contrast to the layer-specific commissural sprouting observed in rats, in which the overwhelming majority of mossy cell axons remain within their home territory. These data demonstrate an important species difference in the commissural/associational sprouting response between rats and mice that needs to be taken into account in future studies.

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.

Muscimol-stimulated radiotracer 36 Cl - uptake in synaptoneurosomes was used to investigate the function of the GABA A receptor complex in the CA1-3 area and fascia dentata (granular and molecular layers and hilus) of rats kindled by stimulation, twice a day, of the Schaffer collateral fibers. Two kindled groups were studied: (a) 24 h after the last generalized tonic-clonic seizure [fully kindled (FK) stage] and (b) 28 days after the last generalized seizure (long-term stage). Synaptoneurosomes were prepared in parallel from subslices of the CA1-3 area and fascia dentata. In FK animals, the muscimol-stimulated 36 Cl - uptake was significantly reduced by 21% in the CA1-3 area in comparison with nonstimulated controls, whereas a significant increase of 29% was found in the fascia dentata. Significant changes were no longer present at 4 weeks after the last generalized seizure. The observed changes in muscimol-stimulated 36 Cl - uptake at the FK stage closely parallel the recently observed changes in [ 3 H]muscimol binding in the CA1 area and fascia dentata. These results indicate that kindling causes a transiently decreased GABA A receptor-mediated function in the CA1-3, in contrast to an increased GABA A receptor-mediated function in the fascia dentata

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.