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Cavities in the hippocampus are morphological variants of uncertain significance. Aberrant neurodevelopment along with vascular and inflammatory etiologies have been proposed. We sought to characterize these cavities and their potential risk factors in a marginally housed population, with high rates of viral infection, addiction, and mental illness. (1) The volume of hippocampal cavities (HCavs) is greater in this highly multimorbid population compared to the general population. (2) Conventional vascular risk factors such as greater age and systolic blood pressure are associated with higher HCav volume. (3) Nonprescribed substance-related risk factors such as stimulant use or dependence, and smoking are associated with increased HCav volume independent of vascular risk factors. This is a retrospective analysis of an ongoing prospective study. We analyzed baseline data, including medical history, physical exam, psychiatric diagnosis, and MRI from a total of 375 participants. Hippocampal cavities were defined as spaces isointense to CSF on T1 MRI sequences, bounded on all sides by hippocampal tissue, with a volume of at least 1 mm 3 . Risk factors were evaluated using negative binomial multiple regression. Stimulant use was reported by 87.3% of participants, with stimulant dependence diagnosed in 83.3% of participants. Prevalence of cavities was 71.6%, with a mean total bilateral HCav volume of 13.89 mm 3 . On average, a 1 mmHg greater systolic blood pressure was associated with a 2.17% greater total HCav volume (95% CI = [0.57%, 3.79%], p = .0076), while each cigarette smoked per day trended toward a 2.69% greater total HCav volume (95% CI = [-0.87%, 5.54%], p = .058). A diagnosis of stimulant dependence was associated with a 95.6% greater total HCav volume (95% CI = [5.39%, 263.19%], p = .0335). Hypertension and diagnosis of stimulant dependence were associated with a greater total volume of HCav., (© 2022 Wiley Periodicals LLC.)

Objective: To determine whether serial position scores in verbal memory differentiate hippocampal-related neuropathologic outcomes, we examined these associations in a sample of older adults without dementia who underwent autopsy., Methods: We used data from the Rush Memory and Aging Project, a longitudinal clinical-pathologic cohort study of community-dwelling adults. A total of 701 participants (mean age 82.7, 71.2% female) completed baseline cognitive evaluations and underwent brain autopsy to identify pathologic Alzheimer disease (AD), TDP-43 inclusions (defining limbic-predominant age-related TDP-43 encephalopathy [LATE]), and hippocampal sclerosis. The Consortium to Establish a Registry for Alzheimer's Disease word list memory test immediate recall trials provided serial position scores, which index the proportion of words recalled from the beginning (primacy scores) and end (recency scores) of a word list. Binary and ordinal logistic regressions examined associations between serial position scores and neuropathologic outcomes. Secondary outcomes included Alzheimer dementia and mild cognitive impairment proximate to death., Results: Primacy and recency scores were uncorrelated ( r = 0.07). Each SD of better primacy score was associated with lower likelihood of neuropathologic changes (24% lower LATE, 31% lower pathologic AD, 37% lower hippocampal sclerosis). For pathologic AD, better baseline primacy scores were associated with a 36% lower likelihood of comorbidity with LATE or hippocampal sclerosis. Primacy scores better discriminated between clinical diagnoses proximate to death, including those with mild cognitive impairment compared to no impairment. Recency scores showed weaker or no associations., Conclusions: Primacy scores may be particularly sensitive markers of AD and related hippocampal neuropathologies. The differential predictive value of serial position scores suggests they offer complementary information about disease outcomes in addition to the routinely used total recall scores., (© 2020 American Academy of Neurology.)

The hippocampus is a key brain region that participates in a range of cognitive and affective functions, and is involved in the etiopathogenesis of numerous neuropsychiatric disorders. The structural complexity and functional diversity of the hippocampus suggest the existence of structural and functional subdivisions within this structure. For the first time, we parcellated the human hippocampus with two independent data sets, each of which consisted of 198 T1-weighted structural magnetic resonance imaging (sMRI) images of healthy young subjects. The method was based on gray matter volume (GMV) covariance, which was quantified by a bivariate voxel-to-voxel linear correlation approach, as well as a multivariate masked independent component analysis approach. We subsequently interrogated the relationship between the GMV covariance patterns and the functional connectivity patterns of the hippocampal subregions using sMRI and resting-state functional MRI (fMRI) data from the same participants. Seven distinct GMV covariance-based subregions were identified for bilateral hippocampi, with robust reproducibility across the two data sets. We further demonstrated that the structural covariance patterns of the hippocampal subregions had a correspondence with the intrinsic functional connectivity patterns of these subregions. Together, our results provide a topographical configuration of the hippocampus with converging structural and functional support. The resulting subregions may improve our understanding of the hippocampal connectivity and functions at a subregional level, which provides useful parcellations and masks for future neuroscience and clinical research on the structural and/or functional connectivity of the hippocampus., (© 2019 Wiley Periodicals, Inc.)

Whether hippocampal neurogenesis persists throughout life in the human brain is not fully resolved. Here, we demonstrate that hippocampal neurogenesis is persistent through the tenth decade of life and is detectable in patients with mild cognitive impairments and Alzheimer's disease. In a cohort of 18 participants with a mean age of 90.6 years, Nestin + Sox2 + neural progenitor cells (NPCs) and DCX + neuroblasts and immature neurons were detected, but their numbers greatly varied between participants. Nestin + cells localize in the anterior hippocampus, and NPCs, neuroblasts, and immature neurons are evenly distributed along the anterior to posterior axis. The number of DCX + PCNA + cells is reduced in mild cognitive impairments, and higher numbers of neuroblasts are associated with better cognitive status. The number of DCX + PCNA + cells correlates with functional interactions between presynaptic SNARE proteins. Our results suggest that hippocampal neurogenesis persists in the aged and diseased human brain and that it is possibly associated with cognition., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Persons who are homeless or marginally housed exhibit significant cognitive dysfunction, with memory being the most impaired domain. Hippocampal subfield volumes have been found to differentially relate to component processes of memory. The neural correlates of memory have not been previously examined in marginalized persons who are understudied and underserved. We examined whether hippocampal subfields and entorhinal cortex volumes are uniquely related to indices of verbal episodic memory using the Hopkins Verbal Learning Test - Revised., Method: Data was used from a large sample of community dwelling homeless and marginally housed adults (N = 227). Regression analyses were conducted to examine hippocampal subfield volumes (CA1, CA3, CA4, dentate gyrus, subiculum) and entorhinal cortex, and their associations with measures of verbal immediate recall, learning slope, and verbal delayed recall., Results: Greater CA3 subfield volume was associated with better performance on an index of encoding (immediate recall), but only in older individuals. Greater CA1 and subiculum volumes were associated with better performance on immediate and delayed recall (measures that tap into retrieval processes), but not with learning slope (a more pure index of encoding). Entorhinal cortex volume was related to all components of memory beyond total hippocampal volume., Conclusions: Our results suggest common neuroanatomical correlates of memory dysfunction in large sample of marginalized persons, and these are uniquely related to different components of memory. These findings have clinical relevance for marginalized populations and theoretical relevance to the growing literature on functional specialization of the hippocampal subfields., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Schizophrenia is associated with poor cognitive function and elevated cardiometabolic disease risk. These health concerns may exacerbate neurocognitive dysfunction associated with hippocampal abnormalities, particularly hippocampal volume reductions. Regular exercise is thought to improve symptom severity, reduce depression, and improve cognition in schizophrenia, and may trigger exercise-mediated hippocampal growth. The potential for the benefits of exercise for treatment-resistant schizophrenia patients has not been clearly assessed. This study aims to assess the effect of exercise on hippocampal plasticity and clinical outcomes in chronic schizophrenia., Methods: Seventeen DSM-IV criteria schizophrenia or schizoaffective disorder patients completed a customized moderate intensity 12-week aerobic or weight-bearing exercise program. Adherence rates were 83% ± 9.4%) with 70% of participants completing the entire exercise program. Concomitant neuroimaging, clinical and cognitive assessments were obtained at baseline and 12-weeks., Results: At follow-up, symptom severity scores (t(16) = -16.8, p. ≤ 0.0001) and social functioning (t(16) = 4.4, p. = 0.0004) improved. A trend for improved depression scores (t(16) = -2.0, p. = 0.06) with no change in anxiety, or extrapyramidal symptoms were seen. Hippocampal volume increased (t(16) = -2.54, p. = 0.02), specifically in the left CA-1 field (F(16) = -2.33, p. = 0.03). Hippocampal vascular volume was unchanged. Change in hippocampal volume and vascular volume was not significantly correlated with change in symptom severity or affect scores., Conclusions: Adjunct exercise may accelerate symptom improvement in treatment-resistant psychosis patients. While the underlying mechanism remains unclear, these results indicate that chronic schizophrenia patients experience hippocampal plasticity in response to exercise., Study Registration: Clinical Trials.govNCT01392885., (Copyright © 2018 Elsevier B.V. All rights reserved.)

We previously reported that higher body mass index (BMI) was associated with greater hippocampal glutamate+glutamine in people with bipolar disorder (BD), but not in non-BD healthy comparator subjects (HSs). In the current report, we extend these findings by examining the impact of BD diagnosis and BMI on hippocampal volumes and the concentrations of several additional neurochemicals in 57 early-stage BD patients and 31 HSs. Using 3-T magnetic resonance imaging and magnetic resonance spectroscopy, we measured bilateral hippocampal volumes and the hippocampal concentrations of four neurochemicals relevant to BD: N-acetylaspartate+N-acteylaspartylglutamate (tNAA), creatine+phosphocreatine (Cre), myoinositol (Ins) and glycerophosphocholine+phosphatidylcholine (Cho). We used multivariate factorial analysis of covariance to investigate the impact of diagnosis (patient vs HS) and BMI category (normal weight vs overweight/obese) on these variables. We found a main effect of diagnosis on hippocampal volumes, with patients having smaller hippocampi than HSs. There was no association between BMI and hippocampal volumes. We found diagnosis and BMI effects on hippocampal neurochemistry, with patients having lower Cre, Ins and Cho, and overweight/obese subjects having higher levels of these chemicals. In patient-only models that controlled for clinical and treatment variables, we detected an additional association between higher BMI and lower tNAA that was absent in HSs. To our knowledge, this was the first study to investigate the relative contributions of BD diagnosis and BMI to hippocampal volumes, and only the second to investigate their contributions to hippocampal chemistry. It provides further evidence that diagnosis and elevated BMI both impact limbic brain areas relevant to BD.

The objective of this longitudinal magnetic resonance (MR) imaging study was to examine the effects of endurance training on hippocampal and grey matter volumes in schizophrenia patients and healthy controls. 20 chronic schizophrenia patients and 21 age- and gender-matched healthy controls underwent 3months of endurance training (30min, 3 times per week). 19 additionally recruited schizophrenia patients played table soccer ("foosball" in the USA) over the same period. MR imaging with 3D-volumetric T1-weighted sequences was performed on a 3T MR scanner at baseline, after 6weeks and after the 3-month intervention and 3 additional training-free months. In addition to voxel-based morphometry (VBM), we performed manual and automatic delineation of the hippocampus and its substructures. Endurance capacity and psychopathological symptoms were measured as secondary endpoints. No significant increases in the volumes of the hippocampus or hippocampal substructures were observed in schizophrenia patients or healthy controls. However, VBM analyses displayed an increased volume of the left superior, middle and inferior anterior temporal gyri compared to baseline in schizophrenia patients after the endurance training, whereas patients playing table soccer showed increased volumes in the motor and anterior cingulate cortices. After the additional training-free period, the differences were no longer present. While endurance capacity improved in exercising patients and healthy controls, psychopathological symptoms did not significantly change. The subtle changes in the left temporal cortex indicate an impact of exercise on brain volumes in schizophrenia. Subsequent studies in larger cohorts are warranted to address the question of response variability of endurance training., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: We previously reported that patients with early-stage bipolar disorder, but not healthy comparison controls, had body mass index (BMI)-related volume reductions in limbic brain areas, suggesting that the structural brain changes characteristic of bipolar disorder were more pronounced with increased weight., Aims: To determine whether the most consistently reported neurochemical abnormality in bipolar disorder, increased glutamate/glutamine (Glx), was also more prominent with higher BMI., Method: We used single-voxel proton magnetic resonance spectroscopy to measure hippocampal Glx in 51 patients with first-episode mania (mean BMI = 24.1) and 28 healthy controls (mean BMI = 23.3)., Results: In patients, but not healthy controls, linear regression demonstrated that higher BMI predicted greater Glx. Factorial ANCOVA showed a significant BMI × diagnosis interaction, confirming a distinct effect of weight on Glx in patients., Conclusions: Together with our volumetric studies, these results suggest that higher BMI is associated with more pronounced structural and neurochemical limbic brain changes in bipolar disorder, even in early-stage patients with low obesity rates., (© The Royal College of Psychiatrists 2016.)

Schizophrenia patients treated with olanzapine, or other second-generation antipsychotics, frequently develop metabolic side-effects, such as glucose intolerance and increased adiposity. We previously observed that modeling these adverse effects in rodents also resulted in hippocampal shrinkage. Here, we investigated the impact of olanzapine treatment, and the beneficial influence of routine exercise, on the neurosecretion machinery of the hippocampus. Immunodensities and interactions of three soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins (syntaxin-1, synaptosome-associated protein of 25kDa (SNAP-25) and vesicle-associated membrane protein (VAMP)), synaptotagmin and complexins-1/2 were quantified in the hippocampus of sedentary and exercising rats exposed over 9weeks to vehicle (n=28) or olanzapine (10mg/kg/day, n=28). In addition, brain sections from subgroups of sedentary animals (n=8) were co-immunolabeled with antibodies against vesicular GABA (VGAT) and glutamate (VGLUT1) transporters, along with syntaxin-1, and examined by confocal microscopy to detect selective olanzapine effects within inhibitory or excitatory terminals. Following olanzapine treatment, sedentary, but not exercising rats showed downregulated (33-50%) hippocampal densities of SNARE proteins and synaptotagmin, without altering complexin levels. Strikingly, these effects had no consequences on the amount of SNARE protein-protein interactions. Lower immunodensity of presynaptic proteins was associated with reduced CA1 volume and glucose intolerance. Syntaxin-1 depletion appeared more prominent in VGAT-positive terminals within the dentate gyrus, and in non-VGAT/VGLUT1-overlapping areas of CA3. The present findings suggest that chronic exposure to olanzapine may alter hippocampal connectivity, especially in inhibitory terminals within the dentate gyrus, and along the mossy fibers of CA3. Together with previous studies, we propose that exercise-based therapies might be beneficial for patients being treated with olanzapine., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Reduced hippocampal volume in schizophrenia is a well-replicated finding. New imaging techniques allow delineation of hippocampal subfield volumes. Studies including predominantly chronic patients demonstrate differences between subfields in sensitivity to illness, and in associations with clinical features. We carried out a cross-sectional and longitudinal study of first episode, sub-chronic, and chronic patients, using an imaging strategy that allows for the assessment of multiple hippocampal subfields., Methods: Hippocampal subfield volumes were measured in 34 patients with schizophrenia (19 first episode, 6 sub-chronic, 9 chronic) and 15 healthy comparison participants. A subset of 10 first episode and 12 healthy participants were rescanned after six months., Results: Total left hippocampal volume was smaller in sub-chronic (p = 0.04, effect size 1.12) and chronic (p = 0.009, effect size 1.42) patients compared with healthy volunteers. The CA2-3 subfield volume of chronic patients was significantly decreased (p = 0.009, effect size 1.42) compared to healthy volunteers. The CA4-DG volume was significantly reduced in all three patient groups compared to healthy group (all p < 0.005). The two affected subfield volumes were inversely correlated with severity of negative symptoms (p < 0.05). There was a small, but statistically significant decline in left CA4-DG volume over the first six months of illness (p = 0.01)., Conclusions: Imaging strategies defining the subfields of the hippocampus may be informative in linking symptoms and structural abnormalities, and in understanding more about progression during the early phases of illness in schizophrenia.

Numerous studies have reported that the hippocampus in schizophrenia patients is reduced in volume compared to the normal population. Antipsychotic medications have had mixed benefits in maintaining hippocampal volume or reversing volume loss. Recent evidence indicates that routine aerobic exercise represents a promising intervention for reversing hippocampal loss and cognitive deficits. In the present study, we measured the effects of chronic treatment with olanzapine and daily exercise on the hippocampal volumes of rats. Adult female rats were treated during the week with either olanzapine (10mg/kg) or vehicle for 9 consecutive weeks. Subgroups of animals were provided access to exercise running wheels for 1 or 3h per day during the same period, or were sedentary. Metabolic indices, including glucose tolerance, were measured on a weekly basis. At the conclusion of the study, brains were perfused and hippocampal sections were Nissl stained. Total hippocampal volume was measured using the Cavalieri estimator. Treatment with olanzapine caused a significant decrease in hippocampal volume in sedentary rats. However, exercise was able to reverse most of this volume loss. The hippocampal sub-regions of the dentate gyrus and CA1 were most strongly affected by olanzapine and exercise. Of interest, there was a strong and highly significant negative correlation between glucose intolerance and hippocampal volume, whereby greater glucose intolerance was associated with a smaller hippocampal volume. These findings indicate that exercise may have beneficial effects on the hippocampus when antipsychotic medication can contribute to changes in volume., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

Introduction: Small hippocampi and impaired memory are common in patients with psychosis and brain-derived neurotrophic factor (BDNF) plays a critical role in hippocampal neuroplasticity and memory. A common BDNF allele (Val66Met) has been the focus of numerous studies but results from the few BDNF-imaging studies are complex and contradictory. The objective of this study was to determine the association between Val66Met and hippocampal volume in patients with first episode psychosis. Secondary analyses explored age-related associations and the relationship between Val66Met and memory., Method: Hippocampal volume and BDNF genotyping were obtained for 58 patients with first-episode psychosis and 39 healthy volunteers. Patients were recruited from an early psychosis program serving a catchment-area population., Results: Hippocampal volume was significantly smaller in patients than controls (F(1,92)=4.03, p<0.05) and there was a significant group-by-allele interaction (F(1,92)=3.99, p<0.05). Hippocampal volume was significantly smaller in patients than controls who were Val-homozygotes but no group differences were found for Met carriers. Findings were not affected by diagnosis, antipsychotic medication, or age, and there was no change in hippocampal volume during a one-year follow-up. Val-homozygous patients had worse immediate and delayed memory than their Met counterparts., Conclusions: Results suggest the effects of the BDNF Val66Met allele may be different in patients with psychosis than in healthy adults. Hippocampal volume in patient and control Met allele carriers was very similar suggesting that illness-related factors have minimal influence in this group. In contrast, Val homozygosity was related to smaller hippocampi and poorer memory functioning only in patients with psychosis., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Context: Hippocampal volume is lower than expected in patients with schizophrenia; however, whether this represents a fixed deficit is uncertain. Exercise is a stimulus to hippocampal plasticity., Objective: To determine whether hippocampal volume would increase with exercise in humans and whether this effect would be related to improved aerobic fitness., Design: Randomized controlled study., Setting: Patients attending a day hospital program or an outpatient clinic., Patients or Other Participants: Male patients with chronic schizophrenia and matched healthy subjects., Interventions: Aerobic exercise training (cycling) and playing table football (control group) for a period of 3 months., Main Outcome Measures: Magnetic resonance imaging of the hippocampus. Secondary outcome measures were magnetic resonance spectroscopy, neuropsychological (Rey Auditory Verbal Learning Test, Corsi block-tapping test), and clinical (Positive and Negative Syndrome Scale) features., Results: Following exercise training, relative hippocampal volume increased significantly in patients (12%) and healthy subjects (16%), with no change in the nonexercise group of patients (-1%). Changes in hippocampal volume in the exercise group were correlated with improvements in aerobic fitness measured by change in maximum oxygen consumption (r = 0.71; P = .003). In the schizophrenia exercise group (but not the controls), change in hippocampal volume was associated with a 35% increase in the N-acetylaspartate to creatine ratio in the hippocampus. Finally, improvement in test scores for short-term memory in the combined exercise and nonexercise schizophrenia group was correlated with change in hippocampal volume (r = 0.51; P < .05)., Conclusion: These results indicate that in both healthy subjects and patients with schizophrenia hippocampal volume is plastic in response to aerobic exercise.

Background: Hippocampal volume reduction is a well replicated finding in schizophrenia. Evidence indicates a contribution of genetic and environmental factors, especially the influence of obstetric complications to this volume reduction. The aim of this study was to compare hippocampal volume of schizophrenic patients as well as and their relatives with control subjects and to quantify the additional contribution of obstetric complications., Methods: T1 weighted MRI brain scans of 50 schizophrenic patients, 88 first-degree relatives and 53 healthy control subjects were used to perform volumetric measurements on the left and right hippocampus. A set of clinical measures including obstetric complications were recorded for all family members., Results: Numerically our measurements revealed a hippocampal volume reduction in schizophrenic patients (left: -14%, right: -15%) and, although less pronounced, in their unaffected relatives (left: -6%, right: -10%). Noted differences in hippocampal volume between schizophrenic patients and controls were only significant for the left side. Hippocampal volumes of patients and their relatives with obstetric complications were reduced bilaterally., Conclusions: Hippocampal volume reduction is present in schizophrenic patients and their first-degree relatives, suggesting an influence of genetic factors. In addition, however, obstetric complications have also been shown to play a major role.

Background: Previous studies have reported that hippocampal volumes correlate with symptom severity in schizophrenia. This longitudinal study measured changes in symptoms and hippocampal volume in patients switched from typical antipsychotics to olanzapine., Methods: MRI scans were acquired from patients with chronic schizophrenia (n=10) and healthy volunteers (n=20). At baseline, patients were treated with typical antipsychotics for at least one year, then switched to olanzapine, and rescanned approximately one year later., Results: Olanzapine treatment resulted in no significant change in right or left hippocampal volume. Individual changes in right hippocampal volume correlated significantly with changes in symptoms., Conclusions: Hippocampal volume change may serve as a marker of symptom change in patients on olanzapine.

Recent studies indicate that levels of presynaptic proteins are altered in the post-mortem brain in schizophrenia. In particular, the hippocampus exhibits reduced levels of synaptophysin and the SNARE protein SNAP-25. The effects of treatment with antipsychotic drugs on levels of SNAP-25 in the hippocampus remains unknown. To determine the effects of typical antipsychotic drugs on levels of synaptophysin and SNAP-25 in the hippocampus, rats were treated with chlorpromazine, haloperidol or trifluoperazine for 21 d. Quantitative immunohistochemistry was used to measure immunoreactivity within the trisynaptic circuit of the hippocampus. Trifluoperazine decreased synaptophysin within the Schaffer collateral region of the radiatum lacunosum in CA1, while haloperidol and chlorpromazine increased SNAP-25 throughout the trisynaptic pathway of the hippocampus, with strongest effects in the mossy fibre region of CA3. These results indicate that presynaptic proteins represent a potential molecular substrate for the effects of antipsychotic drugs on hippocampal synaptic connectivity.

Background: Converging neuroimaging and postmortem evidence indicates synaptic terminals are abnormal in schizophrenia. A putative molecular mechanism implicates abnormalities of proteins involved in the presynaptic secretory machinery, including the modulator proteins complexin I and complexin II., Objectives: To determine the amount and distribution of complexin proteins in the hippocampus of subjects with schizophrenia, in parallel with markers for excitatory and inhibitory nerve terminals. The functional implications were also investigated., Design: We used immunocytochemistry to study complexin I and complexin II proteins in hippocampus, as well as the vesicular transporters for gamma-aminobutyric acid (GABA) and for glutamate. Immunocytochemical findings were correlated with cognitive function assessed through medical record review. To further explore the implications of the human findings, we studied rats exposed to haloperidol, amphetamine, and ketamine as well as rats trained in memory tasks., Subjects: We studied hippocampal sections from 12 subjects with schizophrenia and 12 subjects with no known neuropsychiatric disorder., Results: The absolute values and ratio of the hippocampal presynaptic proteins complexin II-complexin I were lower in subjects with schizophrenia. Disturbances in the complexin proteins in subjects with schizophrenia were greater than those observed for vesicular gamma-aminobutyric acid or vesicular glutamate transporters. The lower complexin II-complexin I ratio in several hippocampal subfields in subjects with schizophrenia was inversely correlated with the severity of antemortem cognitive impairment. In contrast, the hippocampal complexin II-complexin I ratio was higher in rats trained in a memory task compared with untrained rats. Treatment of rats with antipsychotic drugs or with the psychotomimetic drugs amphetamine or ketamine did not alter the complexin II-complexin I ratio., Conclusions: The pathology of hippocampal complexin proteins might play an important role in schizophrenia, especially concerning cognitive disturbances.

Reductions in SNAP-25 immunohistochemistry were found after removing the glutamatergic and cholinergic inputs to the rat hippocampus. SNAP-25 levels were normalised by 1 month after afferent lesions. Surprisingly, a superimposed cholinergic lesions did not affect the return to normal SNAP-25 levels after a long-term entorhinal cortex lesion. It is concluded that changes in SNAP-25 may represent early markers of synaptic loss following afferent lesions to the hippocampus.

Background: The human hippocampus becomes visible during the first trimester and folds to form the hippocampal fissure (HF) in the second trimester. The walls of this fissure fuse by 30 weeks, although small residual cavities can occur if development is disrupted. The primary purpose of this study was to determine if hippocampal fissures are evident in schizophrenia. A second goal was to assess the association between HF size and premorbid and clinical features of the illness., Methods: Magnetic resonance imaging scans were obtained on 33 patients with first-episode schizophrenia and 19 healthy volunteers. Hippocampal fissures were measured using semi-automated procedures, and hippocampi were manually traced. Birth history and premorbid functioning were assessed using maternal report., Results: Patients had a significantly larger mean HF volume and a nonsignificantly smaller hippocampal volume. Hippocampal fissure size was significantly associated with poor educational achievement and with anxiety-depression symptoms during the onset of illness. Smaller hippocampal size was associated with poor premorbid adjustment., Conclusions: Larger HF size and an association between low educational achievement and enlarged HFs suggest abnormal neurodevelopment in schizophrenia. The association between HF size and anxiety-depression symptoms suggests that hippocampal abnormalities underlying HF dilatation may be a predisposing factor for increased stress sensitivity.

In vitro studies have consistently demonstrated a link between cholinergic neurotransmission and amyloid precursor protein metabolism, although few studies have examined such a relationship in vivo and none have been conducted in primate species. The purpose of this study was to test the hypothesis that a reduction in cholinergic activity in neocortical and hippocampal areas consequent upon destruction of ascending cholinergic projections may lead to long-term changes in levels of amyloid precursor protein in these target areas in a primate species. The status of three synaptic proteins associated with neurotransmitter release, synaptophysin, syntaxin and SNAP-25, was also been examined. Selective immunolesions of the basal forebrain cholinergic projections led to increases in amyloid precursor protein-like immunoreactivity in hippocampus and cortex, measured 8 months postlesion. Furthermore, reductions in cortical and hippocampal SNAP-25, but not syntaxin or synaptophysin, immunoreactivity were observed. These results imply that the reduced cholinergic activity characteristic of Alzheimer's disease may contribute to the continuing emergence of neuropathology in addition to the well-known association with cognitive dysfunction.

Regional abnormalities of brain connectivity may be an important substrate for the expression of schizophrenia, a severe form of mental illness. Brain imaging and postmortem morphometric studies indicate hippocampal structure is abnormal in schizophrenia. To study molecular components of hippocampal connectivity the presynaptic proteins SNAP-25 and synaptophysin were assayed in postmortem samples. Immunocytochemical studies indicated reduced SNAP-25 immunoreactivity in schizophrenia compared to controls, particularly in the terminal fields of entorhinal cortex projections. Although there were no overall changes in synaptophysin immunoreactivity, in the granule cell layer of the dentate gyrus synaptophysin immunoreactivity was increased in schizophrenia. These results indicate that disconnection of a subset of hippocampal circuitry from the entorhinal cortex, as well as intrinsic changes in hippocampal connectivity, may contribute to the mechanism of illness in schizophrenia.

We quantified by microdensitometry the immunoreactivity (IR) to monoclonal antibodies (SP6, SP12, SP15 and SP18) against various synaptic proteins in the molecular layers of the dentate gyrus, CA4, CA3, CA1, subiculum and entorhinal cortex in Alzheimer's disease (AD), Lewy body variant of AD (LBV) and diffuse Lewy body disease (DLBD). A significant decrease in SP6 IR was observed in almost all regions in AD (28.4-70.1%, mean 41.3%), LBV (19.0-42.5%, mean 26.8%) and DLBD (19.9-31.7%, mean 27.1%) compared to controls. In addition, SP6 IR in the outer molecular layer of the dentate gyrus was strongly correlated with tangle count in the entorhinal cortex (r = -0.70, P < 0.002), suggesting loss of perforant pathway projection. Although the decrease in SP12 and SP15 IR was less pronounced, the mean values were decreased in dementia. Furthermore, SP12 and SP15 labeled a large number of neuritic plaques, and SP15 occasionally stained cortical LBs. The present findings indicate (i) that in the hippocampal-entorhinal formation, the decrease of synapse protein IR in AD is more severe than that in LBV and DLBD, (ii) that synaptic markers detect a subset of dystrophic neurites in the plaques and (iii) that synapse proteins are involved in the formation of cortical LBs.

Immunostaining of synaptic terminals was studied in the hippocampus of 26 patients who had surgical resections for intractable temporal lobe epilepsy. Two monoclonal antibodies (EP10 and SP12) reactive with distinct synaptic antigens were used on paraffin-embedded tissues. The results indicated qualitative reductions on synaptic terminals in CA4 and other regions where cell loss is reported. The inner molecular layer of the dentate gyrus was observed to have increased synaptic immunostaining. Synaptic terminal loss in CA4 and redistribution in the molecular layer were most frequent in cases with hippocampal sclerosis. However, both forms of synaptic pathology were also noted in most cases where the pathological findings were classified as indefinite, and in some cases associated with mass lesions of the temporal lobe. These results support the importance of neuronal loss and synaptic reorganization as possible mechanisms of illness in epilepsy. They also indicate that synaptic immunostaining may be a useful adjunct to routine neuropathological diagnostic techniques.

Studies of the molecular composition of the abnormal neuritic processes of the plaques in Alzheimer's disease (AD) have shown that these structures are immunoreactive with antibodies against growth-related molecules, synaptic/axonal proteins, and cytoskeletal proteins. These studies suggest that a subpopulation of abnormal neurites in the plaque are sprouting axons that eventually degenerate. To test this hypothesis further we studied the regional distribution of plaques in the hippocampus using a panel of monoclonal antibodies against synaptic proteins. With these antibodies we found a greater proportion of immunoreactive plaques compared to previous studies where a monoclonal antibody against synaptophysin was used. The most sensitive antibodies to detect neuritic plaques were SP11 and anti-p65, and the largest number of positive plaques was found in the entorhinal cortex and CA1 region. These results further support the theory that synaptic and axonal damage are involved in plaque formation in AD.