Hippocampus In Schizophrenia Research Articles

Upregulated solute-carrier family genes in the hippocampus of schizophrenia can be rescued by antipsychotic medications

Background and hypothesisOur previous studies have found that functional changes in the hippocampal circuit from dentate gyrus (DG) to cornu ammonis 3 and 1 (CA3, CA1) are highly associated with schizophrenia (SZ). However, no studies have explored the genetic expression across the three and two human hippocampal subfields (DG-CA3-CA1 and CA3-CA1) between subjects with SZ and healthy controls (CT). Study designWe matched cohorts between CT (n = 13) and SZ (n = 13). Among SZ, 6 subjects were on antipsychotics (AP) while 7 were off AP. We combined RNA-seq data from all three and two hippocampal subfields and performed differentially expressed gene analyses across DG-CA3-CA1 and CA3-CA1 affected by either SZ or AP. Study resultsWe found that differentially expressed genes (DEGs) from effects of SZ and AP across DG-CA3-CA1 and CA3-CA1 were highly associated with gene ontology terms related to hormonal and immune signaling, cellular mitosis and apoptosis, ion and amino acid transports, and protein modification and degradation. Additionally, we found that multiple genes related to solute-carrier family and immune signaling were significantly upregulated across DG-CA3-CA1 and CA3-CA1 in patients with SZ relative to CT, and AP consistently and robustly repressed the expression of these upregulated genes in the DG-CA3-CA1 and CA3-CA1 from subjects with SZ. ConclusionsTogether, these data suggest that the upregulated solute-carrier family genes in the hippocampus might have important roles in the pathophysiology of SZ, and that AP may reduce the symptoms of psychosis in SZ via rescuing the solute-carrier gene expression.

Behavioral as well as hippocampal transcriptomic and microglial responses differ across sexes in adult mouse offspring exposed to a dual genetic and environmental challenge

IntroductionA wide range of positive, negative, and cognitive symptoms compose the clinical presentation of schizophrenia. Schizophrenia is a multifactorial disorder in which genetic and environmental risk factors interact for a full emergence of the disorder. Infectious challenges during pregnancy are a well-known environmental risk factor for schizophrenia. Also, genetic variants affecting the function of fractalkine signaling between neurons and microglia were linked to schizophrenia. Translational animal models recapitulating these complex gene-environment associations have a great potential to untangle schizophrenia neurobiology and propose new therapeutic strategies. MethodsGiven that genetic variants affecting the function of fractalkine signaling between neurons and microglia were linked to schizophrenia, we compared the outcomes of a well-characterized model of maternal immune activation induced using the viral mimetic polyinosinic:polycytidylic acid (Poly I:C) in wild-type versus fractalkine receptor knockout mice. Possible behavioral and immune alterations were assessed in male and female offspring during adulthood. Considering the role of the hippocampus in schizophrenia, microglial analyses and bulk RNA sequencing were performed within this region to assess the neuroimmune dynamics at play. Males and females were examined separately. ResultsOffspring exposed to the dual challenge paradigm exhibited symptoms relevant to schizophrenia and unpredictably to mood disorders. Males displayed social and cognitive deficits related to schizophrenia, while females mainly presented anxiety-like behaviors related to mood disorders. Hippocampal microglia in females exposed to the dual challenge were hypertrophic, indicative of an increased surveillance, whereas those in males showed on the other end of the spectrum blunted morphologies with a reduced phagocytosis. Hippocampal bulk-RNA sequencing further revealed a downregulation in females of genes related to GABAergic transmission, which represents one of the main proposed causes of mood disorders. ConclusionsBuilding on previous results, we identified in the current study distinctive behavioral phenotypes in female mice exposed to a dual genetic and environmental challenge, thus proposing a new model of neurodevelopmentally-associated mood and affective symptoms. This paves the way to future sex-specific investigations into the susceptibility to developmental challenges using animal models based on genetic and immune vulnerability as presented here.

Excitatory and inhibitory imbalances in the trisynaptic pathway in the hippocampus in schizophrenia: a postmortem ultrastructural study.

A preponderance of evidence suggests that the hippocampus is a key region of dysfunction in schizophrenia. Neuroimaging and other studies indicate a relationship between hippocampal dysfunction and the degree of psychosis. Clinical data indicate hyperactivity in the hippocampus that precedes the onset of psychosis, and is correlated with symptom severity. In this study, we sought to identify circuitry at the electron microscopic level that could contribute to region-specific imbalances in excitation and inhibition in the hippocampus in schizophrenia. We used postmortem tissue from the anterior hippocampus from patients with schizophrenia and matched controls. Using stereological techniques, we counted and measured synapses, postsynaptic densities (PSDs), and evaluated size, number and optical density of mitochondria and parvalbumin-containing interneurons in key nodes of the trisynaptic pathway. Compared to controls, the schizophrenia group had decreased numbers of inhibitory synapses in CA3 and increased numbers of excitatory synapses in CA1; together, this indicates deficits in inhibition and an increase in excitation. The thickness of the PSD was larger in excitatory synapses in CA1, suggesting greater synaptic strength. In the schizophrenia group, there were fewer mitochondria in the dentate gyrus and a decrease in the optical density, a measure of functional integrity, in CA1. The number and optical density of parvalbumin interneurons were lower in CA3. The results suggest region-specific increases in excitatory circuitry, decreases in inhibitory neurotransmission and fewer or damaged mitochondria. These results are consistent with the hyperactivity observed in the hippocampus in schizophrenia in previous studies.

Aberrant intra- and internetwork functional connectivity patterns of the anterior and posterior hippocampal networks in schizophrenia.

Schizophrenia is associated with abnormal hippocampal structure and function. Available evidence suggests that the anterior and posterior hippocampus are differentially affected by schizophrenia pathology. This study was designed to provide new insight into the anterior and posterior hippocampus in schizophrenia from the perspective of functional connectivity. Based on resting-state functional magnetic resonance imaging data of 71 schizophrenia patients and 74 normal controls, we utilized a data-driven approach to functionally segment the hippocampus into anterior and posterior segments and then investigated the functional connectivity patterns within and between the two hippocampal networks at the network, edge, and nodal levels. We found that schizophrenia patients showed hyperconnectivity of both the anterior and posterior hippocampal networks. We also observed that the network alterations appear somewhat greater in the anterior hippocampal network than the posterior network, the left side than the right, and the intranetwork connectivity than the internetwork connectivity. The results reveal convergent and divergent intranetwork and internetwork connectivity patterns of the anterior and posterior hippocampus in schizophrenia, providing novel and important insights into the mechanisms of hippocampal pathology in schizophrenia.

Impact of adapted physical activity on hippocampal N-Acetyl Aspartate in patients with schizophrenia

IntroductionAdapted physical activity (APA) has beneficial neurobiological impact but the underlying pathophysiological mechanisms remain poorly described. APA is currently recognized as an adjuvant therapy to antipsychotic treatments in patients with schizophrenia (SCZs) to reduce the severity of negative symptoms and cognitive impairment. SCZs exhibit hippocampal N-acetylaspartate (NAA) reduction, a marker of neuronal viability and integrity whose concentrations can be assessed by proton magnetic resonance spectroscopy (1H-MRS).ObjectivesThe purpose of this study was to evaluate the impact of remote physical activity (e-APA) via the web on the NAA relative variations in the left hippocampus in SCZs compared to a patient control group benefiting from an health education program (HE). This study concerns one of the secondary objectives of the PEPsy V@SI study co-financed by the Pierre Deniker Foundation, the European Union and the Normandy Region within the framework of the FEDER/FSE 2014-2020 operational program.MethodsThirty-five SCZs were randomized in the e-APA active group or in the control group (HE). Participants received the interventions during 16 weeks, with two visioconference sessions per week. A 1H-MRS sequence positioned on the left hippocampus (MRI-3T) was acquired before and after both interventions. Absolute NAA concentrations in the left hippocampus were obtained using Osprey software after partial volume correction. After checking the quality criteria, the spectra of 6 SCZs in the e-APA group and 8 SCZs in the HE group were analyzed. To test the difference between interventions on the NAA relative variations, a Wilcoxon-Mann-Whitney test and effect size were performed. Paired Wilcoxon tests were used in each group before and after the interventions.ResultsNo significant difference was found in NAA relative variations in the left hippocampus between the e-APA group and the HE group (p = 0.18), although the effect size was 0.38 (considered as moderate). However, a trend towards an increase of NAA was observed in the e-APA group (before intervention: 12.08 International Units (I.U); after: 13.81 I.U) (p = 0.06) but not in the HE group (before intervention: 13.75 I.U ; after: 13.85 I.U) (p = 0.84).ConclusionsOur results showed a NAA significant increase in SCZs after an e-APA program, indicating a beneficial impact of e-APA on neuronal viability that might reflect an hippocampal plasticity. However, this increase did not differ significantly between active and control groups probably due to a weak statistical power.Disclosure of InterestL. Metivier: None Declared, F. Briend: None Declared, M. Tréhout: None Declared, L. Bigot: None Declared, G. Quarck: None Declared, A. Herbinet: None Declared, E. Leroux: None Declared, S. Dollfus Consultant of: Fabre,Gedeon,Roche and Takeda, inivited Conferences by Lundbeck, Otsuka, Janssen ; at contracts with Prophase MedAvances and NeuroCogTrials

Exploration of the relationship between hippocampus and immune system in schizophrenia based on immune infiltration analysis.

Immune dysfunction has been implicated in the pathogenesis of schizophrenia (SZ). Despite previous studies showing a broad link between immune dysregulation and the central nervous system of SZ, the exact relationship has not been completely elucidated. With immune infiltration analysis as an entry point, this study aimed to explore the relationship between schizophrenia and the immune system in more detail from brain regions, immune cells, genes, and pathways. Here, we comprehensively analyzed the hippocampus (HPC), prefrontal cortex (PFC), and striatum (STR) between SZ and control groups. Differentially expressed genes (DEGs) and functional enrichment analysis showed that three brain regions were closely related to the immune system. Compared with PFC and STR, there were 20 immune-related genes (IRGs) and 42 immune pathways in HPC. The results of immune infiltration analysis showed that the differential immune cells in HPC were effector memory T (Tem) cells. The correlation of immune-related DEGs (IDEGs) and immune cells further analysis showed that NPY, BLNK, OXTR, and FGF12, were moderately correlated with Tem cells. Functional pathway analysis indicated that these four genes might affect Tem by regulating the PI3K-AKT pathway and the neuroactive ligand-receptor interaction pathway. The receiver operating characteristic curve (ROC) analysis results indicated that these four genes had a high diagnostic ability (AUC=95.19%). Finally, the disease animal model was successfully replicated, and further validation was conducted using the real-time PCR and the western blot. These results showed that these gene expression changes were consistent with our previous expression profiling. In conclusion, our findings suggested that HPC in SZ may be more closely related to immune disorders and modulate immune function through Tem, PI3K-Akt pathway, and neuroactive ligand-binding receptor interactions. To the best of our knowledge, the Immucell AI tool has been applied for the first time to analyze immune infiltration in SZ, contributing to a better understanding of the role of immune dysfunction in SZ from a new perspective.

Transdiagnostic Role of Glutamate and White Matter Damage in Neuropsychiatric Disorders: A Systematic Review

IntroductionNeuropsychiatric disorders including Generalized Anxiety Disorder (GAD), Obsessive-Compulsive Disorder (OCD), Major Depressive Disorder (MDD), Bipolar Disorder (BD), and Schizophrenia (SZ) have been considered distinct categories of diseases despite their overlapping characteristics and symptomatology.ObjectivesWe aimed to provide an in-depth review elucidating the role of glutamate/Glx and white matter (WM) abnormalities from a transdiagnostic perspective.MethodsThe PubMed online database was searched for studies published between 2010 and 2021. After careful screening, 399 studies were included.ResultsThe findings point to decreased levels of glutamate in the Anterior Cingulate Cortex in both SZ and BD, whereas Glx is elevated in the Hippocampus in SZ and MDD. With regard to WM abnormalities, the Corpus Callosum and superior Longitudinal Fascicle were the most consistently identified brain regions showing decreased fractional anisotropy (FA) across all the reviewed disorders, except GAD. Additionally, the Uncinate Fasciculus was found to be affected in all the reviewed disorders, except OCD. Decreased FA was also found in the inferior Longitudinal Fasciculus, inferior Fronto-Occipital Fasciculus, Thalamic Radiation, and Corona Radiata in SZ, BD, and MDD. Decreased FA in the Fornix and Corticospinal Tract were found in BD and SZ patients. The Cingulum and Anterior Limb of Internal Capsule exhibited decreased FA in MDD and SZ patients.ConclusionsThe results suggest a gradual increase in severity from GAD to SZ defined by the number of brain regions with WM abnormality which may be partially caused by abnormal glutamate levels. WM damage could thus be considered a potential marker of some of the main neuropsychiatric disorders.DisclosureNo significant relationships.

Structural and Functional Deviations of the Hippocampus in Schizophrenia and Schizophrenia Animal Models.

Schizophrenia is a grave neuropsychiatric disease which frequently onsets between the end of adolescence and the beginning of adulthood. It is characterized by a variety of neuropsychiatric abnormalities which are categorized into positive, negative and cognitive symptoms. Most therapeutical strategies address the positive symptoms by antagonizing D2-dopamine-receptors (DR). However, negative and cognitive symptoms persist and highly impair the life quality of patients due to their disabling effects. Interestingly, hippocampal deviations are a hallmark of schizophrenia and can be observed in early as well as advanced phases of the disease progression. These alterations are commonly accompanied by a rise in neuronal activity. Therefore, hippocampal formation plays an important role in the manifestation of schizophrenia. Furthermore, studies with animal models revealed a link between environmental risk factors and morphological as well as electrophysiological abnormalities in the hippocampus. Here, we review recent findings on structural and functional hippocampal abnormalities in schizophrenic patients and in schizophrenia animal models, and we give an overview on current experimental approaches that especially target the hippocampus. A better understanding of hippocampal aberrations in schizophrenia might clarify their impact on the manifestation and on the outcome of this severe disease.

AMPA receptors in schizophrenia: A systematic review of postmortem studies on receptor subunit expression and binding

BackgroundWhile altered expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type receptor has been reported in postmortem studies of schizophrenia, these findings are inconsistent. Therefore, we aimed to systematically review postmortem studies that investigated AMPA receptor expressions in schizophrenia. MethodsA systematic literature search was conducted for postmortem studies that measured AMPA receptor subunit expressions or receptor bindings in schizophrenia compared to healthy individuals on February 3, 2021, using Medline and Embase. ResultsA total of 39 relevant articles were identified from 1360 initial reports. The dorsolateral prefrontal cortex (DLPFC) was the most investigated region (15 studies), followed by the medial temporal lobe (8 studies). For the DLPFC, 4/15 studies (26.7%) showed increased AMPA receptor binding or subunit expression in patients with schizophrenia compared to that in controls, especially in GRIA1 and GRIA4, 2/15 studies (13.3%) reported a decrease, particularly in GRIA2, and 8/15 studies (56.7%) found no significant differences. A decreased expression or receptor binding was observed in 6/8 studies (75.0%) in the subregions of the hippocampus in patients with schizophrenia compared to that in controls, whereas the other two studies found no significant differences. ConclusionPublished data have reported decreased subunit expression or receptor binding in the hippocampus in schizophrenia. These findings were inconsistent in other brain regions, which might be due to the heterogeneity of this population, various study design, physiological changes after death, and limited number of studies. Future in vivo studies are warranted to examine AMPA receptor expressions in human brains, together with their comprehensive clinical characterization.

Linking proteomic alterations in schizophrenia hippocampus to NMDAr hypofunction in human neurons and oligodendrocytes.

Glutamatergic neurotransmission dysfunction and the early involvement of the hippocampus have been proposed to be important aspects of the pathophysiology of schizophrenia. Here, we performed proteomic analysis of hippocampus postmortem samples from schizophrenia patients as well as neural cells-neurons and oligodendrocytes-treated with MK-801, an NMDA receptor antagonist. There were similarities in processes such as oxidative stress and apoptotic process when comparing hippocampus samples with MK-801-treated neurons, and in proteins synthesis when comparing hippocampus samples with MK-801-treated oligodendrocytes. This reveals that studying the effects of glutamatergic dysfunction in different neural cells can contribute to a better understanding of what it is observed in schizophrenia patients' postmortem brains.

Incomplete hippocampal inversion in schizophrenia: prevalence, severity, and impact on hippocampal structure

Incomplete hippocampal inversion (IHI) is an anatomical variant of the human brain resulting from an arrest in brain development, especially prevalent in the left hemisphere. We hypothesized that IHI is more common in schizophrenia and contributes to the well-known hippocampal structural differences. We studied 199 schizophrenia patients and 161 healthy control participants with 3 T MRI to establish IHI prevalence and the relationship of IHI with hippocampal volume and asymmetry. IHI was more prevalent (left hemisphere: 15% of healthy control participants, 27% of schizophrenia patients; right hemisphere: 4% of healthy control participants, 10% of schizophrenia patients) and more severe in schizophrenia patients compared to healthy control participants. Severe IHI cases were associated with a higher rate of automated segmentation failure. IHI contributed to smaller hippocampal volume and increased R > L volume asymmetry in schizophrenia. The increased prevalence and severity of IHI supports the neurodevelopmental model of schizophrenia. The impact of this developmental variant deserves further exploration in studies of the hippocampus in schizophrenia.

Abnormalities in the copper transporter CTR1 in postmortem hippocampus in schizophrenia: A subregion and laminar analysis

Dysbindin-1 modulates copper transport, which is crucial for cellular homeostasis. Several brain regions implicated in schizophrenia exhibit decreased levels of dysbindin-1, which may affect copper homeostasis therein. Our recent study showed decreased levels of dysbindin-1, the copper transporter-1 (CTR1) and copper in the substantia nigra in schizophrenia, providing the first evidence of disrupted copper transport in schizophrenia. In the present study, we hypothesized that there would be lower levels of dysbindin-1 and CTR1 in the hippocampus in schizophrenia versus a comparison group. Using semi-quantitative immunohistochemistry for dysbindin1 and CTR1, we measured the optical density in a layer specific fashion in the hippocampus and entorhinal cortex in ten subjects with schizophrenia and ten comparison subjects. Both regions were richly immunolabeled for CTR1 and dysbindin1 in both groups. In the superficial layers of the entorhinal cortex, CTR1 immunolabeled neuropil and cells showed lower optical density values in patients versus the comparison group. In the molecular layer of the dentate gyrus, patients had higher optical density values of CTR1 versus the comparison group. The density and distribution of dysbindin-1 immunolabeling was similar between groups. These laminar specific alterations of CTR1 in schizophrenia suggest abnormal copper transport in those locations.

Hippocampal Resting State Functional Connectivity in Patients With Schizophrenia and Unaffected Family Members.

The hippocampus is an important candidate region in the study of functional connectivity alterations in schizophrenia (SZ) given its role as a functional hub for multiple brain networks. Although studies have implicated the hippocampus in SZ, no studies have compared hippocampal functional connectivity in healthy participants, patients with SZ, and unaffected family members (UAFMs). Patients and UAFM likely share biomarkers associated with susceptibility to SZ; the study of UAFM may also reveal compensatory markers. Patients with SZ, UAFM, and healthy control (HC) participants underwent resting state magnetic resonance imagingty and completed the Wisconsin Card Sort Task (WCST) as a measure of general cognitive function. We compared functional coupling with a hippocampus seed across the three groups. SZ and UAFM groups shared reductions in connectivity between the hippocampus and the striatum relative to HC. We also identified a significant positive correlation between WCST errors and hippocampal-striatal connectivity in the UAFM group. Hippocampal-striatal rsFC may be associated with familial susceptibility to SZ and with subtle cognitive deficits in the UAFM of individuals with SZ.

N-methyl-D-aspartate receptor subunit 1 regulates neurogenesis in the hippocampal dentate gyrus of schizophrenia-like mice.

N-methyl-D-aspartate receptor hypofunction is the basis of pathophysiology in schizophrenia. Blocking the N-methyl-D-aspartate receptor impairs learning and memory abilities and induces pathological changes in the brain. Previous studies have paid little attention to the role of the N-methyl-D-aspartate receptor subunit 1 (NR1) in neurogenesis in the hippocampus of schizophrenia. A mouse model of schizophrenia was established by intraperitoneal injection of 0.6 mg/kg MK-801, once a day, for 14 days. In N-methyl-D-aspartate-treated mice, N-methyl-D-aspartate was administered by intracerebroventricular injection in schizophrenia mice on day 15. The number of NR1-, Ki67- or BrdU-immunoreactive cells in the dentate gyrus was measured by immunofluorescence staining. Our data showed the number of NR1-immunoreactive cells increased along with the decreasing numbers of BrdU- and Ki67-immunoreactive cells in the schizophrenia groups compared with the control group. N-methyl-D-aspartate could reverse the above changes. These results indicated that NR1 can regulate neurogenesis in the hippocampal dentate gyrus of schizophrenia mice, supporting NR1 as a promising therapeutic target in the treatment of schizophrenia. This study was approved by the Experimental Animal Ethics Committee of the Ningxia Medical University, China (approval No. 2014-014) on March 6, 2014.

Parvalbumin promoter hypermethylation in postmortem brain in schizophrenia.

Deficits of brain parvalbumin (PV) are a consistent finding in schizophrenia and models of psychosis. We investigated whether this is associated with abnormal PV gene (PVALB) methylation in the brain in schizophrenia. Bisulfite pyrosequencing was used to determine cytosine (CpG) methylation in a PVALB promoter sequence. Greater PVALB methylation was found in schizophrenia hippocampus, while no differences were observed in prefrontal cortex. LINE-1 methylation, a measure of global methylation, was also elevated in both regions in schizophrenia, although the PVALB change was independent of this effect. These results provide the first evidence that PVALB promoter methylation is abnormal in schizophrenia and suggest that this epigenetic finding may relate to the reduction of PV expression seen in the disease.

Evidence for regional hippocampal damage in patients with schizophrenia.

Schizophrenia patients show cognitive and mood impairments, including memory loss and depression, suggesting damage in the brain regions. The hippocampus is a brain structure that is significantly involved in memory and mood function and shows impairment in schizophrenia. In the present study, we examined the regional hippocampal changes in schizophrenia patients using voxel-based morphometry (VBM), Freesurfer, and proton magnetic resonance spectroscopy (1H MRS) procedures. 1H MRS and high-resolution T1-weighted magnetic resonance imaging were collected in both healthy control subjects (N = 28) and schizophrenia patients (N = 28) using 3-Tesla whole body MRI system. Regional hippocampal volume was analyzed using VBM and Freesufer procedures. The relative ratios of the neurometabolites were calculated using linear combination model (LCModel). Compared to controls, schizophrenia patients showed significantly decreased gray matter volume in the hippocampus. Schizophrenia patients also showed significantly reduced glutamate (Glu) and myo-inositol (mI) ratios in the hippocampus. Additionally, significant positive correlation between gray matter volume and Glu/tCr was also observed in the hippocampus in schizophrenia. Our findings provide an evidence for a possible association between structural deficits and metabolic alterations in schizophrenia patients.

47. Effect of Antipsychotic Medication on Hippocampal Function and Neurochemistry: A Longitudinal Study in Patients With Schizophrenia

Background: Our prior studies with PET and 15O have shown associations between hippocampal function and treatment response to antipsychotic drugs (APDs). In addition, we found elevated hippocampal glutamate in unmedicated patients with schizophrenia (SZ) but not in medicated. Here, we use a longitudinal design to evaluate the relationship between glutamate and function of the hippocampus in SZ in relation to treatment response to APDs. Methods: 34 SZ were scanned while unmedicated and after 6 weeks of APD. 23 matched healthy controls were also scanned twice six weeks apart. Imaging was done on a 3T head-only scanner equipped with a circularly polarized transmit/receive head coil. A high-resolution structural scan was acquired using the 3D T1-weighted magnetization-prepared rapid acquisition gradient-echo sequence ([TR/TE/ TI] = 2300/3.93/1100ms; flip angle = 12°; 256 × 256 matrix; and 1mm isotropic voxels). Eyes open resting-state fMRI (rsfMRI) was acquired using the gradient recalled echo-planar-imaging sequence (TR/TE = 2000/30ms, flip angle = 70°, field of view = 192mm3, 6mm slice thickness, 1mm gap, 30 axial slices, 225 acquisitions). rsfMRI data were preprocessed and analyzed using CONN toolbox and SPM12. Resting-state magnetic resonance spectroscopy was collected with a voxel prescribed in the left hippocampus (2.7 × 1.5 × 1cm) using the PRESS sequence optimized for glutamate (TR/TE = 2000/80ms, spectral bandwidth = 1024 points, 640 averages) and analyzed in jMRUI. A median split was used to separate SZ into treatment responders and non-responders (calculated as percent change in BPRS positive symptoms). Results: Before treatment, those who subsequently responded to treatment were characterized by significantly elevated glutamate levels compared to both healthy controls and nonresponders. Treatment responders but not non-responders or healthy controls glutamate levels significantly decreased over the 6-week course of treatment. Additionally, treatment responders demonstrated reduced hippocampal blood oxygen-level-dependent (BOLD) fMRI signal compared to healthy controls and nonresponders. Conclusion: Before treatment, both hippocampal glutamate levels and hippocampal BOLD signal appear to differentiate good treatment responders from poor treatment responders.

Molecular evidence of synaptic pathology in the CA1 region in schizophrenia.

Alterations of postsynaptic density (PSD)95-complex proteins in schizophrenia ostensibly induce deficits in synaptic plasticity, the molecular process underlying cognitive functions. Although some PSD95-complex proteins have been previously examined in the hippocampus in schizophrenia, the status of other equally important molecules is unclear. This is especially true in the cornu ammonis (CA)1 hippocampal subfield, a region that is critically involved in the pathophysiology of the illness. We thus performed a quantitative immunoblot experiment to examine PSD95 and several of its associated proteins in the CA1 region, using post mortem brain samples derived from schizophrenia subjects with age-, sex-, and post mortem interval-matched controls (n=20/group). Our results indicate a substantial reduction in PSD95 protein expression (−61.8%). Further analysis showed additional alterations to the scaffold protein Homer1 (Homer1a: +42.9%, Homer1b/c: −24.6%), with a twofold reduction in the ratio of Homer1b/c:Homer1a isoforms (P=0.011). Metabotropic glutamate receptor 1 (mGluR1) protein levels were significantly reduced (−32.7%), and Preso, a protein that supports interactions between Homer1 or PSD95 with mGluR1, was elevated (+83.3%). Significant reduction in synaptophysin (−27.8%) was also detected, which is a validated marker of synaptic density. These findings support the presence of extensive molecular abnormalities to PSD95 and several of its associated proteins in the CA1 region in schizophrenia, offering a small but significant step toward understanding how proteins in the PSD are altered in the schizophrenia brain, and their relevance to overall hippocampal and cognitive dysfunction in the illness.

Progression from selective to general involvement of hippocampal subfields in schizophrenia

Volume deficits of the hippocampus in schizophrenia have been consistently reported. However, the hippocampus is anatomically heterogeneous; it remains unclear whether certain portions of the hippocampus are affected more than others in schizophrenia. In this study, we aimed to determine whether volume deficits in schizophrenia are confined to specific subfields of the hippocampus and to measure the subfield volume trajectories over the course of the illness. Magnetic resonance imaging scans were obtained from Data set 1: 155 patients with schizophrenia (mean duration of illness of 7 years) and 79 healthy controls, and Data set 2: an independent cohort of 46 schizophrenia patients (mean duration of illness of 18 years) and 46 healthy controls. In addition, follow-up scans were collected for a subset of Data set 1. A novel, automated method based on an atlas constructed from ultra-high resolution, post-mortem hippocampal tissue was used to label seven hippocampal subfields. Significant cross-sectional volume deficits in the CA1, but not of the other subfields, were found in the schizophrenia patients of Data set 1. However, diffuse cross-sectional volume deficits across all subfields were found in the more chronic and ill schizophrenia patients of Data set 2. Consistent with this pattern, the longitudinal analysis of Data set 1 revealed progressive illness-related volume loss (~2–6% per year) that extended beyond CA1 to all of the other subfields. This decline in volume correlated with symptomatic worsening. Overall, these findings provide converging evidence for early atrophy of CA1 in schizophrenia, with extension to other hippocampal subfields and accompanying clinical sequelae over time.

Cross-sectional Study of Glutamate in the Anterior Cingulate and Hippocampus in Schizophrenia.

There has been growing support for dysfunctions of the excitatory glutamatergic system and its implications for the psychophysiology of schizophrenia. However, previous studies reported mixed results regarding glutamate concentrations in schizophrenia with varying deviations across brain regions. We used an optimized proton magnetic resonance spectroscopy procedure to measure absolute glutamate concentrations in the left hippocampal region and the anterior cingulate cortex (ACC) in 29 medicated patients with schizophrenia and in 29 control participants without mental disorder. The glutamate concentrations were significantly lower in the ACC but higher in the hippocampus of patients compared to controls. ACC and hippocampal glutamate concentrations correlated positively in patients but not in controls. ACC glutamate was weakly associated with Clinical Global Impression score and duration of illness in patients. Glutamate concentrations in schizophrenia deviate from controls and show associations with disease severity. A higher concentration of hippocampal glutamate in schizophrenia compared to controls is shown. The association between ACC and hippocampus glutamate concentrations in patients with schizophrenia suggests an abnormal coupling of excitatory systems compared to controls as predicted by previous glutamate models of schizophrenia.