Postmortem Schizophrenic Brain Research Articles

Long COVID, neuropsychiatric disorders, psychotropics, present and future.

Long COVID refers to the lingering symptoms which persist or appear after the acute illness. The dominant long COVID symptoms in the two years since the pandemic began (2020-2021) have been depression, anxiety, fatigue, concentration and cognitive impairments with few reports of psychosis. Whether other symptoms will appear later on is not yet known. For example, dopamine-dependent movement disorders generally take many years before first symptoms are seen. Post-stroke depression and anxiety may explain many of the early long COVID cases. Hemorrhagic, hypoxic and inflammatory damages of the central nervous system, unresolved systematic inflammation, metabolic impairment, cerebral vascular accidents such as stroke, hypoxia from pulmonary damages and fibrotic changes are among the major causes of long COVID. Glucose metabolic and hypoxic brain issues likely predispose subjects with pre-existing diabetes, cardiovascular or lung problems to long COVID as well. Preliminary data suggest that psychotropic medications may not be a danger but could instead be beneficial in combating COVID-19 infection. The same is true for diabetes medications such as metformin. Thus, a focus on sigma-1 receptor ligands and glucose metabolism is expected to be useful for new drug development as well as the repurposing of current drugs. The reported protective effects of psychotropics and antihistamines against COVID-19, the earlier reports of reduced number of sigma-1 receptors in post-mortem schizophrenic brains, with many antidepressant and antipsychotic drugs being antihistamines with significant affinity for the sigma-1 receptor, support the role of sigma and histamine receptors in neuroinflammation and viral infections. Literature and data in all these areas are accumulating at a fast rate. We reviewed and discussed the relevant and important literature.

Gene Expression Of Methylation Cycle And Related Genes In Lymphocytes And Brain Of Patients With Schizophrenia And Non-Psychotic Controls.

Some of the biochemical abnormalities underlying schizophrenia, involve differences in methylation and methylating enzymes, as well as other related target genes. We present results of a study of differences in mRNA expression in peripheral blood lymphocytes (PBLs) and post-mortem brains of chronic schizophrenics (CSZ) and non-psychotic controls (NPC), emphasizing the differential effects of sex and antipsychotic drug treatment on mRNA findings. We studied mRNA expression in lymphocytes of 61 CSZ and 49 NPC subjects using qPCR assays with TaqMan probes to assess levels of DNMT, TET, GABAergic, NR3C1, BDNF mRNAs, and several additional targets identified in a recent RNA sequence analysis. In parallel we studied DNMT1 and GAD67 in samples of brain tissues from 19 CSZ, 26 NPC. In PBLs DNMT1 and DNMT3A mRNA levels were significantly higher in male CSZ vs NPC. No significant differences were detected in females. The GAD1, NR3C1 and CNTNAP2 mRNA levels were significantly higher in CSZ than NPC. In CSZ patients treated with clozapine, GAD-1 related, CNTNAP2, and IMPA2 mRNAs were significantly higher than in CSZ subjects not treated with clozapine. Differences between CSZ vs NPC in these mRNAs was primarily attributable to the clozapine treatment. In the brain samples, DNMT1 was significantly higher and GAD67 was significantly lower in CSZ than in NPC, but there were no significant sex differences in diagnostic effects. These findings highlight the importance of considering sex and drug treatment effects in assessing the substantive significance of differences in mRNAs between CSZ and NPC.

Adiponectin receptor2 and HCLS1 associated proteinX-1 levels are altered in postmortem schizophrenic brain

Schizophrenia is a complex mental disorder. Several genetic abnormalities have been identified in individuals with schizophrenia. The present investigation was undertaken to detect novel schizophrenia-related genes in the brain. Complementary DNA (cDNA) microarray technique was used to identify differentially expressed genes in human postmortem brain samples obtained from individuals who had been diagnosed with schizophrenia and matched normals. Compared to hippocampus from normal brains, hippocampus from schizophrenic brains had seventy-four upregulated genes/expressed sequence tags (ESTs) and eighty-seven downregulated genes/ESTs. In the prefrontal cortical region of schizophrenic brains, nineteen genes/ESTs were upregulated, and twenty genes/ESTs were downregulated. Altered genes belonged to several different gene families such as cancer, cell cycle, hematological and infectious diseases. One significantly upregulated gene (HCLS1 associated protein X-1, HAX1) and one significantly downregulated gene (adiponectin receptor2, AdipoR2) were selected for further investigation in an independent set of postmortem schizophrenic and normal temporal cortical samples, using Western blot analyses. Compared to normal brain samples, HAX1 protein levels were higher, and AdipoR2 protein levels were lower in schizophrenic brain samples. We have identified two novel dysregulated schizophrenia-related genes in postmortem human brain – one downregulated gene adiponectin receptor 2 (AdipoR2), and one upregulated gene HCLS1 associated protein X-1 (HAX1). HAX1 and AdipoR2 have not been previously reported to be dysregulated in schizophrenia. Future studies will investigate the role of these genes in the pathophysiology of schizophrenia.

Microglial Activation and Psychotic Disorders: Evidence from Pre-clinical and Clinical Studies.

Clinical and pre-clinical studies have demonstrated an important role of neuroinflammation in the etiology of schizophrenia. While the underlying mechanisms remain poorly understood, there are some studies demonstrating an association between maternal immune activation and behavioral changes in adult offspring and identifying early life infection as a trigger for schizophrenia; in addition, inflammatory markers were found to be increased in the schizophrenic post-mortem brain. During maternal immune activation, pro-inflammatory mediators such as cytokines, chemokines, antibodies, and acute-phase proteins are released in the maternal bloodstream, thus increasing the permeability of the placental barrier and the fetal blood-brain barrier, allowing the inflammatory mediators to enter the fetal brain. In the central nervous system (CNS), these pro-inflammatory mediators are able to activate microglial cells that can release pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6. As a consequence, circulating immune cells may infiltrate the brain, increasing cytokine levels and releasing antibodies that aggravate the neuroinflammation. Neuroinflammation may affect processes that are pivotal for normal brain maturation such as myelination, synaptic pruning, and neuronal remodeling. Microglial cell activation and pro-inflammatory mediators have been extensively studied in schizophrenic post-mortem brain samples. Some results of these investigations demonstrated an increase in microglial activation markers, cytokines, and chemokines in post-mortem brain samples from individuals with schizophrenia. In contrast, there are studies that have demonstrated low levels of microglial activation makers in the schizophrenic post-mortem brain. Thus, based on the important role of neuroinflammation as a trigger in the development of schizophrenia, this chapter aims (1) to enumerate evidence of neuroinflammation and microglial activation from pre-clinical schizophrenia models, (2) to show links between schizophrenia and neuroinflammation in clinical studies, and (3) to identify mechanisms by which microglial activation may influence in the development of schizophrenia.

Parvalbumin Loss Following Chronic Sub-Anesthetic NMDA Antagonist Treatment is Age-Dependent in the Hippocampus: Implications for Modeling NMDA Hypofunction

A marked decrease in parvalbumin (PV), a calcium-binding protein specific to a subset of GABAergic neurons, is a consistent finding in postmortem schizophrenic brain tissue. This reduction is selective to PV and is regionally specific, occurring primarily in the prefrontal cortex and hippocampus (HPC) of patients. Rodent models of NMDA receptor hypofunction utilizing NMDA antagonist treatments – e.g. ketamine (KET) – show schizophrenia-like cognitive and behavioral impairments with parallel changes in PV. While decreased PV is considered a hallmark of neuropathology in schizophrenia, previous work elucidating the effects of KET administration on PV are contradictory, with findings suggesting decreased, increased, or no change in PV expression. Upon close examination of the procedures used across studies, there are two primary inconsistencies, including: (1) the age of animals used; and (2) the timeline of post-treatment tissue collection. To better understand whether these key differences impact observed PV changes, the present study investigated the impact of age and time of sacrifice on chronic KET-induced PV changes in the neocortex and HPC. Our findings suggest an effect of age, but not sacrifice timeline, on PV cell count following 14 days of sub-anesthetic KET treatment. We provide evidence that 1-month-old rats exhibit a significant KET-induced HPC PV decrease, while adult rats show a modest increase in HPC PV following chronic KET. Taken together, we propose that PV is a dynamic marker, and that changes in cell counts – and their interpretation – following NDMA antagonist treatment should be considered in the context of age.

Postmortem evidence of cerebral inflammation in schizophrenia: a systematic review.

Schizophrenia is a psychiatric disorder which has a lifetime prevalence of ~1%. Multiple candidate mechanisms have been proposed in the pathogenesis of schizophrenia. One such mechanism is the involvement of neuroinflammation. Clinical studies, including neuroimaging, peripheral biomarkers and randomized control trials, have suggested the presence of neuroinflammation in schizophrenia. Many studies have also measured markers of neuroinflammation in postmortem brain samples from schizophrenia patients. The objective of this study was to conduct a systematic search of the literature on neuroinflammation in postmortem brains of schizophrenia patients indexed in MEDLINE, Embase and PsycINFO. Databases were searched up until 20th March 2016 for articles published on postmortem brains in schizophrenia evaluating microglia, astrocytes, glia, cytokines, the arachidonic cascade, substance P and other markers of neuroinflammation. Two independent reviewers extracted the data. Out of 5385 articles yielded by the search, 119 articles were identified that measured neuroinflammatory markers in schizophrenic postmortem brains. Glial fibrillary acidic protein expression was elevated, lower or unchanged in 6, 6 and 21 studies, respectively, and similar results were obtained for glial cell densities. On the other hand, microglial markers were increased, lower or unchanged in schizophrenia in 11, 3 and 8 studies, respectively. Results were variable across all other markers, but SERPINA3 and IFITM were consistently increased in 4 and 5 studies, respectively. Despite the variability, some studies evaluating neuroinflammation in postmortem brains in schizophrenia suggest an increase in microglial activity and other markers such as SERPINA3 and IFITM. Variability across studies is partially explained by multiple factors including brain region evaluated, source of the brain, diagnosis, age at time of death, age of onset and the presence of suicide victims in the cohort.

Developmental Age Differentially Mediates the Calcium-Binding Protein Parvalbumin in the Rat: Evidence for a Selective Decrease in Hippocampal Parvalbumin Cell Counts

Local circuit GABAergic neurons, including parvalbumin (PV)-containing basket cells, likely play a key role in the development, physiology, and pathology of neocortical circuits. Regionally selective and well-defined decreases in PV have been described in human postmortem schizophrenic brain tissue in both the hippocampus and prefrontal cortex. Animal models of schizophreniform dysfunction following acute and/or chronic ketamine treatment have also demonstrated decreases in PV expression. Conflicting reports with respect to PV immunoreactivity following acute and chronic ketamine treatments in rodents question the utility of using PV as a biological marker of pathology-related dysfunction. The current literature lacks sufficient and systematic characterization of normative PV expression in pharmacologically and behaviorally naïve rodent tissue. In order to understand developmental changes in PV and its putative role in neuropathology, we examined the baseline distribution of the number of cells expressing this protein at distinct developmental ages. The present study examined PV cell counts across the septotemporal axis of the CA1, CA3, and dentate gyrus (DG) regions of the hippocampus, as well as within the retrosplenial, somatosensory, and prefrontal cortices, in 1-, 6-, and 12-month-old naïve rats. Our findings suggest that the hippocampal PV+ cell number significantly decreases as a function of age with considerable regional (CA1, CA3, and DG) and septotemporal variation, a finding that was specific to the hippocampus. Additionally, we observed a modest increase in PV cell number within the prefrontal (anterior cingulate) cortex, which is in line with findings indicating a delayed developmental maturation of this region. The present work highlights decreases in PV+ cell counts within the hippocampus across development, and points to the need for a greater understanding of the role of PV and local circuit developmental changes, as well as consideration of their development when modeling developmentally related neuropathological disorders (e.g. schizophrenia, autism).

A decrease in protein level and a missense polymorphism of KIF17 are associated with schizophrenia

It has been shown that the dysfunction of N-methyl-d-asparate (NMDA) receptors-mediated neurotransmission plays a role in the pathophysiology of schizophrenia. Especially, GluN2B, a subunit of NMDA receptors, associated trafficking complex is altered in the prefrontal cortex of schizophrenia. The kinesin superfamily motor protein 17 (KIF17) is known as a transporter of NR2B.Previous studies showed that a structural variant of KIF17 gene is associated with a schizophrenic phenotype. Therefore, here we investigated KIF17 levels in postmortem prefrontal cortex in schizophrenia and the association of a missense polymorphism (Ile341Val) in KIF17 with schizophrenia. The protein expression of KIF17 in schizophrenic postmortem brains was significantly lower than that in controls. Next, the association of missense polymorphisms (rs631375, rs13375609, rs522496 and rs2296225) of KIF17 gene in 567 schizophrenia and 710 healthy subjects was examined. Both genotypic distribution and allelic frequency of rs2296225 polymorphism were significantly different between the chronic schizophrenia subjects and controls. However, our findings described above were not replicated with the independent subjects (555 schizophrenia and 814 healthy controls). Furthermore, the two alleles of rs2296225 polymorphism did not affect the mRNA expression of KIF17. These results suggest that the dysfunction of KIF17 might be involved in the pathophysiology of schizophrenia.

Dendritic morphology changes in neurons from the ventral hippocampus, amygdala and nucleus accumbens in rats with neonatal lesions into the prefrontal cortex.

Neonatal prefrontal cortex (nPFC) lesions in rats could be a potential animal model to study the early neurodevelopmental abnormalities associated with the behavioral and morphological brain changes observed in schizophrenia. Morphological alterations in pyramidal neurons from the ventral hippocampus (VH) have been observed in post-mortem schizophrenic brains, mainly because of decreased dendritic arbor and spine density. We assessed the effects of nPFC-lesions on the dendritic morphology of neurons from the VH, basolateral-amygdala (BLA) and the nucleus accumbens (NAcc) in rats. nPFC lesions were made on postnatal day 7 (PD7), after dendritic morphology was studied by the Golgi-Cox stain procedure followed by Sholl analysis at PD35 (prepubertal) and PD60 (adult) ages. We also evaluated the effects of PFC-lesions on locomotor activity caused by a novel environment. Adult animals with nPFC lesions showed a decreased spine density in pyramidal neurons from the VH and in medium spiny cells from the NAcc. An increased locomotion was observed in a novel environment for adult animals with a PFC-lesion. Our results indicate that PFC-lesions alter the neuronal dendrite morphology of the NAcc and the VH, suggesting a disconnection between these limbic structures. The locomotion paradigms suggest that dopaminergic transmission is altered in the PFC lesion model. This could help to understand the consequences of an earlier PFC dysfunction in schizophrenia. To evaluate possible dendritic changes in neonatal prefrontal cortex lesions in schizophrenia-related regions including nucleus accumbens, ventral hippocampus and basolateral amygdala, we used the Golgi-Cox stain samples at PD35 and PD70. Our results suggest that neonatal prefrontal cortex damage alters dendritic parameters in limbic regions, and this has potential implications for schizophrenia.

Reelin influences the expression and function of dopamine D2 and serotonin 5-HT2A receptors: A comparative study

Reelin is an extracellular matrix protein that plays a critical role in neuronal guidance during brain neurodevelopment and in synaptic plasticity in adults and has been associated with schizophrenia. Reelin mRNA and protein levels are reduced in various structures of post-mortem schizophrenic brains, in a similar way to those found in heterozygous reeler mice (HRM). Reelin is involved in protein expression in dendritic spines that are the major location where synaptic connections are established. Thus, we hypothesized that a genetic deficit in reelin would affect the expression and function of dopamine D2 and serotonin 5-HT2A receptors that are associated with the action of current antipsychotic drugs.In this study, D2 and 5-HT2A receptor expression and function were quantitated by using radioligand binding studies in the frontal cortex and striatum of HRM and wild-type mice (WTM). We observed increased expression (p<0.05) in striatum membranes and decreased expression (p<0.05) in frontal cortex membranes for both dopamine D2 and serotonin 5-HT2A receptors from HRM compared to WTM.Our results show parallel alterations of D2 and 5-HT2A receptors that are compatible with a possible hetero-oligomeric nature of these receptors. These changes are similar to changes described in schizophrenic patients and provide further support for the suitability of using HRM as a model for studying this disease and the effects of antipsychotic drugs.

Association study of H2AFZ with schizophrenia in a Japanese case-control sample.

It is widely accepted that malfunction of the N-methyl-D-aspartate (NMDA)-type glutamate receptor may be involved in the pathophysiology of schizophrenia. Several recent microRNA (miRNA) studies have demonstrated that the expression of the glutamate system-related miR-132 and miR-212 is changed in postmortem schizophrenic brains. Here we attempted to obtain further insight into the relationships among schizophrenia, the NMDA receptor, the molecular cascades controlled by these miRNAs and commonly predicted target genes of the two miRNAs. We focused on the H2AFZ (encoding H2A histone family, member Z) gene, whose expression was shown in our screening study to be modified by a schizophrenomimetic NMDA antagonist, phencyclidine. By performing polymerase chain reaction with fluorescent signal detention using the TaqMan system, we examined four tag single nucleotide polymorphisms (SNPs; SNP01-04) located around and within the H2AFZ gene for their genetic association with schizophrenia. The subjects were a Japanese cohort (2,012 patients with schizophrenia and 2,170 control subjects). We did not detect any significant genetic association of these SNPs with schizophrenia in this cohort. However, we observed a significant association of SNP02 (rs2276939) in the male patients with schizophrenia (allelic P = 0.003, genotypic P = 0.008). A haplotype analysis revealed that haplotypes consisting of SNP02-SNP03 (rs10014424)-SNP04 (rs6854536) also showed a significant association in the male patients with schizophrenia (P = 0.018). These associations remained significant even after correction for multiple testing. The present findings suggest that the H2AFZ gene may be a susceptibility factor in male subjects with schizophrenia, and that modification of the H2AFZ signaling pathway warrants further study in terms of the pathophysiology of schizophrenia.

Calcyon stimulates neuregulin 1 maturation and signaling.

Neuregulin1 (NRG1) is a single transmembrane protein that plays a critical role in neural development and synaptic plasticity. Both NRG1 and its receptor, ErbB4, are well-established risk genes of schizophrenia. The NRG1 ecto-domain (ED) binds and activates ErbB4 following proteolytic cleavage of pro-NRG1 precursor protein. Although several studies have addressed the function of NRG1 in brain, very little is known about the cleavage and shedding mechanism. Here we show that the neuronal vesicular protein calcyon is a potent activator and key determinant of NRG1 ED cleavage and shedding. Calcyon stimulates clathrin-mediated endocytosis and endosomal targeting; and its levels are elevated in postmortem brains of schizophrenics. Overexpression of calcyon stimulates NRG1 cleavage and signaling in vivo, and as a result, GABA transmission is enhanced in calcyon overexpressing mice. Conversely, NRG1 cleavage, ErbB4 activity and GABA transmission are decreased in calcyon null mice. Moreover, stimulation of NRG1 cleavage by calcyon was recapitulated in HEK 293 cells suggesting the mechanism involved is cell-autonomous. Finally, studies with site-specific mutants in calcyon and inhibitors for the major sheddases indicate that the stimulatory effects of calcyon on NRG1 cleavage and shedding depend on clathrin-mediated endocytosis, β-secretase 1, and interaction with clathrin adaptor proteins. Together these results identify a novel mechanism for NRG1 cleavage and shedding.

How Nox2-containing NADPH oxidase affects cortical circuits in the NMDA receptor antagonist model of schizophrenia.

Schizophrenia is a complex neuropsychiatric disorder affecting around 1% of the population worldwide. Its mode of inheritance suggests a multigenic neurodevelopmental disorder with symptoms appearing during late adolescence/early adulthood, with its onset strongly influenced by environmental stimuli. Many neurotransmitter systems, including dopamine, glutamate, and gamma-aminobutyric acid, show alterations in affected individuals, and the behavioral and physiological characteristics of the disease can be mimicked by drugs that produce blockade of N-methyl-d-aspartate glutamate receptors (NMDARs). Mounting evidence suggests that drugs that block NMDARs specifically impair the inhibitory capacity of parvalbumin-expressing (PV+) fast-spiking neurons in adult and developing rodents, and alterations in these inhibitory neurons is one of the most consistent findings in the schizophrenic postmortem brain. Disruption of the inhibitory capacity of PV+ inhibitory neurons will alter the functional balance between excitation and inhibition in prefrontal cortical circuits producing impairment of working memory processes such as those observed in schizophrenia. Mechanistically, the effect of NMDAR antagonists can be attributed to the activation of the Nox2-dependent reduced form of nicotinamide adenine dinucleotide phosphate oxidase pathway in cortical neurons, which is consistent with the emerging role of oxidative stress in the pathogenesis of mental disorders, specifically schizophrenia. Here we review the mechanisms by which NMDAR antagonists produce lasting impairment of the cortical PV+ neuronal system and the roles played by Nox2-dependent oxidative stress mechanisms. The discovery of the pathways by which oxidative stress leads to unbalanced excitation and inhibition in cortical neural circuits opens a new perspective toward understanding the biological underpinnings of schizophrenia.

An Emerging Role for TARPs in Neuropsychiatric Disorders

The discovery of glutamate as the principal excitatory neurotransmitter in brain was followed by the identification and molecular cloning of the ionotropic glutamate receptor family, which comprises NMDA, AMPA, and kainate receptors. The AMPA receptor subfamily mediates fast synaptic neurotransmission important to diverse sensory, behavioral, and cognitive processes, including learning and memory. However, excessive AMPA receptor activity and subsequent excitotoxicity underlie central nervous system disorders ranging from stroke to epilepsy. It was hypothesized that the development of AMPA receptor antagonists to dampen aberrant neurotransmission would provide treatments for neurological illnesses. However, clinical trials have shown side effects for these antagonists and suggested a need for greater selectivity. A seminal finding in AMPA receptor biology and neurotransmission was the discovery of stargazin, the protein mutated in stargazer mice, which show absence epilepsy and cerebellar ataxia. Cell biological and physiological studies showed that stargazin is an AMPA receptor auxiliary subunit and controls receptor trafficking, gating, and pharmacology. Subsequent studies have identified a family of related transmembrane AMPA receptor regulator proteins (TARPs). TARPs comprise γ-2 (stargazin), -3, -4, -5, -7, and -8 subunits, which are discretely distributed in specific neuronal and glial populations throughout the brain. Studies involving γ-8 knockout mice, which exhibit deficiencies in hippocampal neurotransmission, underscore the importance of TARPs both in region-specific control of AMPA receptor signaling, and in neurological disease—hippocampal excitotoxicity elicited by the AMPA receptor partial agonist, kainate, is abrogated in γ-8 knockout mice (Tomita et al, 2007). Neuropsychiatric conditions such as schizophrenia, depression, and bipolar disorder are severe, multifactorial brain illnesses of mood, cognition, and behavior whose etiologies remain uncertain. Molecular analyses have found abnormal expression for key components of glutamatergic neurotransmission, including TARPs. Increased and decreased stargazin mRNA expression has been documented in post-mortem schizophrenic and major depressive disorder brains, respectively (Beneyto and Meador-Woodruff, 2006). Silberberg et al (2008) found certain CACNG2 (the gene that encodes stargazin) allelic polymorphisms are associated with improved response to lithium, the classical treatment for bipolar disorder. Furthermore, chronic treatment with the antidepressants desipramine and paroxetine increased AMPA receptor association with stargazin in rat hippocampus (Martinez-Turrillas et al, 2007). Patients with bipolar disorder or schizophrenia have exhibited decreased CACNG2 DNA copy number (Wilson et al, 2006). Yet, increased stargazin mRNA expression has been found in the dorsolateral prefrontal cortex of brains from bipolar disorder patients suggesting a potential regio-specific action for stargazin in this disorder (Silberberg et al, 2008). Furthermore, the PDE 11A knockout mouse, which shows multiple psychiatric illness-related phenotypes, possessed decreased hippocampal expression of both γ-2 and -8 proteins (Kelly et al, 2010). Recent research into neuropsychiatric illnesses has shown an emerging pathological role for TARPs. As TARPs are differentially localized in neuron pathways, targeting individual isoforms may enable selective modulation of specific brain circuits without globally affecting synaptic transmission. However, the feasibility of uniquely targeting specific AMPA receptor complexes has not yet been established.

Opposite effect of phencyclidine on activity-regulated cytoskeleton-associated protein (Arc) in juvenile and adult limbic rat brain regions

The psychotomimetic effect of NMDA antagonists such as phencyclidine (PCP) in humans spurred the hypoglutamatergic theory of schizophrenia. This theory is supported by animal studies demonstrating schizophrenia-like behavioral and molecular changes following PCP administration to adult or neonatal animals. However, schizophrenia is believed to develop in part due to neurodevelopmental dysfunction during adolescence. Therefore, the effects of PCP in juvenile animals may better reflect the pathophysiology of schizophrenia. Here, we compare the effect of PCP (5 mg/kg/day for 5 days) on activity-regulated cytoskeleton-associated protein (Arc) and parvalbumin mRNA expression in juvenile and adult rats. Arc is a marker for excitatory neurotransmission. Parvalbumin is a marker for GABAergic neurotransmission, known to be reduced in postmortem brains of schizophrenics. PCP reduced parvalbumin mRNA expression in the medial prefrontal cortex (mPFC), ventrolateral orbitofrontal cortex (VLO) and shell of the nucleus accumbens (ACCshell) in both juvenile and adult rats. Contrarily, PCP produced opposite effects on Arc mRNA expression in the mPFC, VLO and ACCshell, leading to decreased expression in juvenile and increased expression in adult rats. The differential effect of PCP in juvenile and adult rats may be caused by the immature functional state of the prefrontal cortex in juvenile rats. These results demonstrate differences between the effects of PCP in juvenile and adult rats. The decrease in Arc mRNA in juvenile rats corresponds best with the proposed “hypofrontality” in schizophrenia, suggesting the merits of using PCP in juvenile animals as a model for schizophrenia, as this would relate better to the typical onset and clinical features of schizophrenia.

How DISC1 Regulates Postnatal Brain Development: Girdin Gets In on the AKT

In this issue of Neuron, Kim et al. and Enomoto et al. show that DISC1 plays a key role in regulating postnatal brain development though interaction with Girdin. Girdin in turn regulates AKT signaling. Thus, another facet of the role of DISC1 is established, shedding more light on fundamental brain processes and the developmental basis of major psychiatric disorders.

Decreased dendritic spine density of neurons of the prefrontal cortex and nucleus accumbens and enhanced amphetamine sensitivity in postpubertal rats after a neonatal amygdala lesion

A neonatal basolateral-amygdala (nBLA) lesion in rats could be a potential animal model to study the early neurodevelopmental abnormalities associated with the behavioral and morphological brain changes observed in schizophrenia. Morphological alterations in pyramidal neurons from the prefrontal cortex (PFC) have been observed in postmortem schizophrenic brains, mainly because of decreased dendritic arbor and spine density. We assessed the effects of nBLA-lesion on the dendritic morphology of neurons from the PFC and the nucleus accumbens (NAcc) in rats. nBLA lesions were made on postnatal day 7 (PD7), and later, the dendritic morphology was studied by the Golgi-Cox stain procedure followed by Sholl analysis at PD35 (prepubertal) and PD60 (adult) ages. We also evaluated the effects of the nBLA-lesion on locomotor activity caused by a novel environment, apomorphine, and amphetamine. Adult animals with nBLA lesions showed a decreased spine density in pyramidal neurons from the PFC and in medium spiny cells from the NAcc. An increased locomotion in a novel environment and in amphetamine-treated adult animals with an nBLA-lesion was observed. Our results indicate that nBLA-lesion alters the neuronal dendrite morphology of the NAcc and PFC, suggesting a disconnection between these limbic structures. The locomotion paradigms support the idea that dopaminergic transmission is altered in the nBLA lesion model. This could help to understand the consequences of an earlier amygdala dysfunction in schizophrenia.

No genetic association between the SLC1A2 gene and Japanese patients with schizophrenia

Glutamatergic dysfunction may be a pathophysiological feature in the brains of schizophrenic patients. In addition to glutamate receptors, excitatory amino acid transporters (EAATs) have received much attention because they directly affect glutamatergic neurotransmission by excluding excessive glutamate from the synaptic cleft. Among these, EAAT2 (also known as solute carrier family 1, member 2; SLC1A2) has been widely studied in schizophrenia pathophysiology. During the last decade, we reported significant decreases in EAAT2 mRNA expression in the prefrontal cortex and parahippocampal gyrus in postmortem schizophrenic brains. Previously, a haplotype association between SLC1A2 and Japanese patients with schizophrenia was reported. In this study, we reinvestigated the association between SLC1A2 and schizophrenia by performing a case–control association study with twice as many subjects (401 cases and 407 controls) as compared to a previous study, and especially focused on the region where a previous association with schizophrenia had been shown. Our current results failed to show any significant association with schizophrenia in individual single nucleotide polymorphisms (SNPs), two- and three-SNP-based haplotypes, or with possible pairwise haplotype analysis. SCL1A2 appears not to be a genetic risk factor for schizophrenia.

Apolipoprotein-E gene variants associated with cardiovascular risk factors in antipsychotic recipients

Interest exists in identifying the factors that specifically contribute to the increased prevalence of cardiovascular disease observed in psychiatric disease. The apolipoprotein-E (APOE) gene codes for a protein that has a key role in metabolism of cholesterol and triglycerides, with increased levels of apoE found in specific areas of post-mortem schizophrenic brains. This study investigated whether apoE variants influence the prevalence of cardiovascular risk factors (obesity, diabetes and dyslipidaemia), in patients receiving antipsychotic treatment, due to extension of the risk seen in the general population, but also due to the role of the APOE gene in mediating antipsychotic-induced side effects. Seven polymorphisms (rs741780, rs483082, rs429358, rs7412, rs10119, rs439401 and rs405509) were genotyped in 427 American Caucasian patients who were either receiving, or had been prescribed risperidone. Our results support the hypothesis that APOE gene variants influence the prevalence of diabetes and possibly overweight in psychiatric patients. Unfortunately, due to the cross sectional nature of this study, the contribution of antipsychotic treatment was not determined. These associations warrant prospective study to assess interaction between APOE gene variants and the propensity of antipsychotics to induce cardiovascular risk factors.

A study of monoamine neuronal systems of schizophrenic patients: Using forensic autopsy brains

Studies on autopsy brains of mental illnesses are essential for psychiatric research. Brain materials from forensic autopsy cases have been valuable research resource. We introduced some characteristic neuronal structures of schizophrenic post-mortem brains and normal controls detected using both forensic and pathological autopsy cases and immunohistochemical method. Dopamine-related neuronal structures in schizophrenic cases were investigated by using immunohistochemistry for tyrosine hydroxylase (TH), aromatic l-amino acid decarboxylase (AADC) and phenylethanolamine- N-methyltransferase (PNMT). At the level of the striatum, the number of AADC-positive, but TH-negative neurons ( d-neurons) reduced in schizophrenics compared with controls. In the brainstem structures, we described some morphological findings characteristic to catecholaminergic neurons of the ventral tegmental area of schizophrenic cases and reduction of the number of medullary catecholaminergic neurons. These results might be in accordance with recent reports describing neural stem cell dysfunction in schizophrenic brains. The authors also introduced the first systematic psychiatric brain bank in Japan, the Fukushima Psychiatric Brain Bank, constructed in 1997, and mentioned the necessity for arrangement of brain bank systems to further promote the psychiatric brain research.