Neurons In Schizophrenia Research Articles

Atypical antipsychotics improve dendritic spine pathology in temporal lobe cortex neurons in a developmental rodent model of schizophrenia.

"Dendritic spine pathology" refers to alterations in density and morphology of dendritic spines, crucial in corticolimbic neurons in schizophrenia. These structural neuroplasticity changes contribute to the disease's neurobiological underpinnings, alongside alterations in other brain regions, such as temporal lobe cortices like the auditory cortex (Au1) and the entorhinal cortex (Ent), involved in sensory processing, memory, and learning. The neonatal ventral hippocampus lesion (NVHL) in rats exhibits behavioral abnormalities akin to schizophrenia symptoms and corticolimbic dendritic spine pathology, mitigated by atypical antipsychotic drugs (AADs) like risperidone (RISP) and olanzapine (OLZ). This study investigated NVHL-induced dendritic spine pathology in Au1 and Ent, evaluating RISP and OLZ effects. NVHL induced dendritic spine pathology mainly by reducing the dendritic spine density in Au1 and Ent neurons; both RISP and OLZ mitigated it, increasing dendritic spine density and mushroom spine population, the ones related with synaptic strengthening, while decreasing stubby spine population. These findings underscore the role of impaired neuroplasticity in the temporal lobe cortices in schizophrenia pathophysiology and highlight the relevance of the NVHL model for studying neuroplasticity mechanisms in the disease. They also contribute to the growing understanding of targeting structural and functional neuroplasticity for novel drugs in the pharmacotherapy of the disease.

Adenosine Metabolism Pathway Alterations in Frontal Cortical Neurons in Schizophrenia.

Schizophrenia is a neuropsychiatric illness characterized by altered neurotransmission, in which adenosine, a modulator of glutamate and dopamine, plays a critical role that is relatively unexplored in the human brain. In the present study, postmortem human brain tissue from the anterior cingulate cortex (ACC) of individuals with schizophrenia (n = 20) and sex- and age-matched control subjects without psychiatric illness (n = 20) was obtained from the Bronx-Mount Sinai NIH Brain and Tissue Repository. Enriched populations of ACC pyramidal neurons were isolated using laser microdissection (LMD). The mRNA expression levels of six key adenosine pathway components-adenosine kinase (ADK), equilibrative nucleoside transporters 1 and 2 (ENT1 and ENT2), ectonucleoside triphosphate diphosphohydrolases 1 and 3 (ENTPD1 and ENTPD3), and ecto-5'-nucleotidase (NT5E)-were quantified using real-time PCR (qPCR) in neurons from these individuals. No significant mRNA expression differences were observed between the schizophrenia and control groups (p > 0.05). However, a significant sex difference was found in ADK mRNA expression, with higher levels in male compared with female subjects (Mann-Whitney U = 86; p < 0.05), a finding significantly driven by disease (t(17) = 3.289; p < 0.05). Correlation analyses also demonstrated significant associations (n = 12) between the expression of several adenosine pathway components (p < 0.05). In our dementia severity analysis, ENTPD1 mRNA expression was significantly higher in males in the "mild" clinical dementia rating (CDR) bin compared with males in the "none" CDR bin (F(2, 13) = 5.212; p < 0.05). Lastly, antipsychotic analysis revealed no significant impact on the expression of adenosine pathway components between medicated and non-medicated schizophrenia subjects (p > 0.05). The observed sex-specific variations and inter-component correlations highlight the value of investigating sex differences in disease and contribute to the molecular basis of schizophrenia's pathology.

Dysfunctional Parvalbumin Neurons in Schizophrenia and the Pathway to the Clinical Application of Kv3 Channel Modulators.

Based on the pathophysiological changes observed in schizophrenia, the gamma-aminobutyric acid (GABA) hypothesis may facilitate the development of targeted treatments for this disease. This hypothesis, mainly derived from postmortem brain results, postulates dysfunctions in a subset of GABAergic neurons, particularly parvalbumin-containing interneurons. In the cerebral cortex, the fast spike firing of parvalbumin-positive GABAergic interneurons is regulated by the Kv3.1 and Kv3.2 channels, which belong to a potassium channel subfamily. Decreased Kv3.1 levels have been observed in the prefrontal cortex of patients with schizophrenia, prompting the investigation of Kv3 channel modulators for the treatment of schizophrenia. However, biomarkers that capture the dysfunction of parvalbumin neurons are required for these modulators to be effective in the pharmacotherapy of schizophrenia. Electroencephalography and magnetoencephalography studies have demonstrated impairments in evoked gamma oscillations in patients with schizophrenia, which may reflect the dysfunction of cortical parvalbumin neurons. This review summarizes these topics and provides an overview of how the development of therapeutics that incorporate biomarkers could innovate the treatment of schizophrenia and potentially change the targets of pharmacotherapy.

Expression of activity-regulated transcripts in pyramidal neurons across the cortical visuospatial working memory network in unaffected comparison individuals and individuals with schizophrenia

Visuospatial working memory (vsWM), which is impaired in schizophrenia (SZ), is mediated by multiple cortical regions including the primary (V1) and association (V2) visual, posterior parietal (PPC) and dorsolateral prefrontal (DLPFC) cortices. In these regions, parvalbumin (PV) or somatostatin (SST) GABA neurons are altered in SZ as reflected in lower levels of activity-regulated transcripts. As PV and SST neurons receive excitatory inputs from neighboring pyramidal neurons, we hypothesized that levels of activity-regulated transcripts are also lower in pyramidal neurons in these regions. Thus, we quantified levels of four activity-regulated, pyramidal neuron-selective transcripts, namely adenylate cyclase-activating polypeptide-1 (ADCYAP1), brain-derived neurotrophic factor (BDNF), neuronal pentraxin-2 (NPTX2) and neuritin-1 (NRN1) mRNAs, in V1, V2, PPC and DLPFC from unaffected comparison and SZ individuals. In SZ, BDNF and NPTX2 mRNA levels were lower across all four regions, whereas ADCYAP1 and NRN1 mRNA levels were lower in V1 and V2. The regional pattern of deficits in BDNF and NPTX2 mRNAs was similar to that in transcripts in PV and SST neurons in SZ. These findings suggest that lower activity of pyramidal neurons expressing BDNF and/or NPTX2 mRNAs might contribute to alterations in PV and SST neurons across the vsWM network in SZ.

Correlation between the number of interstitial neurons of the white matter and number of neurons within cortical layers: Histological analyses in postnatal macaque.

We have examined the number and distribution of NeuN-immunoreactive cortical white matter interstitial cells (WMICs) and compared them to the neurons in layers 1-6 across the overlying cortex in coronal sections from postnatal macaques. The data have been gathered from over 300 selected regions at gyral crowns, at sulci, and at linear regions of the cortex where we also determined cortical layer thicknesses: standard thicknesses and tangential thicknesses. Cortical thicknesses and cell numbers showed variability according to gyral, linear, or sulcal regions. In spite of these variations, our standardized cell numbers in layers 1 to 6b and interstitial cells underlying layer 6b-white matter boundary have shown a consistent correlation between the number of WMICs and the number of layer 5 and 6a cortical neurons on all cortical regions studied: for each WMIC, there are on the order of five cortical neurons in layer 5 and approximately three cortical neurons in layer 6a, irrespective of the origins of the selected cortical area or whether they are from gyral, linear, or sulcal regions. We propose that the number of interstitial neurons in the postnatal macaque cortex is correlated to the density of neurons within layers 5 and 6a and, from a clinical perspective, the change in density or distribution of interstitial neurons in schizophrenia or epilepsy may in fact be linked to the number of layers 5 and 6a neurons.

Adenosine Receptor mRNA Expression in Frontal Cortical Neurons in Schizophrenia.

Schizophrenia is a devastating neuropsychiatric disorder associated with the dysregulation of glutamate and dopamine neurotransmitter systems. The adenosine system is an important neuroregulatory system in the brain that modulates glutamate and dopamine signaling via the ubiquitously expressed adenosine receptors; however, adenosine A1 and A2A receptor (A1R and A2AR) mRNA expression is poorly understood in specific cell subtypes in the frontal cortical brain regions implicated in this disorder. In this study, we assayed A1R and A2AR mRNA expression via qPCR in enriched populations of pyramidal neurons, which were isolated from postmortem anterior cingulate cortex (ACC) tissue from schizophrenia (n = 20) and control (n = 20) subjects using laser microdissection (LMD). A1R expression was significantly increased in female schizophrenia subjects compared to female control subjects (t(13) = -4.008, p = 0.001). A1R expression was also significantly decreased in female control subjects compared to male control subjects, suggesting sex differences in basal A1R expression (t(17) = 2.137, p = 0.047). A significant, positive association was found between dementia severity (clinical dementia rating (CDR) scores) and A2AR mRNA expression (Spearman's r = 0.424, p = 0.009). A2AR mRNA expression was significantly increased in unmedicated schizophrenia subjects, suggesting that A2AR expression may be normalized by chronic antipsychotic treatment (F(1,14) = 9.259, p = 0.009). Together, these results provide novel insights into the neuronal expression of adenosine receptors in the ACC in schizophrenia and suggest that receptor expression changes may be sex-dependent and associated with cognitive decline in these subjects.

Attention Deficit-Hyperactivity Disorder (ADHD): From Abnormal Behavior to Impairment in Synaptic Plasticity.

Attention deficit-hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high incidence in children and adolescents characterized by motor hyperactivity, impulsivity, and inattention. Magnetic resonance imaging (MRI) has revealed that neuroanatomical abnormalities such as the volume reduction in the neocortex and hippocampus are shared by several neuropsychiatric diseases such as schizophrenia, autism spectrum disorder and ADHD. Furthermore, the abnormal development and postnatal pruning of dendritic spines of neocortical neurons in schizophrenia, autism spectrum disorder and intellectual disability are well documented. Dendritic spines are dynamic structures exhibiting Hebbian and homeostatic plasticity that triggers intracellular cascades involving glutamate receptors, calcium influx and remodeling of the F-actin network. The long-term potentiation (LTP)-induced insertion of postsynaptic glutamate receptors is associated with the enlargement of spine heads and long-term depression (LTD) with spine shrinkage. Using a murine model of ADHD, a delay in dendritic spines' maturation in CA1 hippocampal neurons correlated with impaired working memory and hippocampal LTP has recently reported. The aim of this review is to summarize recent evidence that has emerged from studies focused on the neuroanatomical and genetic features found in ADHD patients as well as reports from animal models describing the molecular structure and remodeling of dendritic spines.

Disease-specific differences in gene expression, mitochondrial function and mitochondria-endoplasmic reticulum interactions in iPSC-derived cerebral organoids and cortical neurons in schizophrenia and bipolar disorder

We compared transcriptomic profiles of cerebral organoids differentiated from induced pluripotent stem cells of eight schizophrenia and eight bipolar disorder patients to identify genes that were differentially expressed in cerebral organoids between two disorders. Gene ontology analysis showed relative up-regulation in schizophrenia organoids of genes related to response to cytokines, antigen binding and clathrin-coated vesicles, while showing up-regulation in bipolar disorder of genes involved in calcium binding. Gene set enrichment analysis revealed enrichment in schizophrenia of genes involved in mitochondrial and oxidative phosphorylation while showing enrichment in bipolar disorder of genes involved in long term potentiation and neuro-transporters. We compared mitochondrial function in cerebral organoids from schizophrenia and bipolar disorder subjects and found that while schizophrenia organoids showed deficits in basal oxygen consumption rate and ATP production when compared to healthy control organoids, while bipolar disorder organoids did not show these deficits. Gene ontology analyses also revealed enrichment in bipolar disorder of genes in ion binding and regulation of transport. Experiments examining the interaction between mitochondria and endoplasmic reticulum in cortical neurons from bipolar disorder subjects showed a significantly lower number of contact sites between mitochondria and endoplasmic reticulum when compared to cortical neurons from schizophrenia patients. These results point to disease-specific deficits in mitochondrial respiration in schizophrenia and in mitochondrial-endoplasmic reticulum interactions in bipolar disorder.

Alteration of the Functional Connectivity of the Cortical Areas Characterized by the Presence of Von Economo Neurons in Schizophrenia, a Pilot Study.

Von Economo neurons (VENs) are rod, stick, or corkscrew cells mostly located in layer V of the frontoinsular and anterior cingulate cortices. VENs are projection neurons related to human-like social cognitive abilities. Post-mortem histological studies found VEN alterations in several neuropsychiatric disorders, including schizophrenia (SZ). This pilot study aimed to evaluate the role of VEN-containing areas in shaping patterns of resting-state brain activation in patients with SZ (n = 20) compared to healthy controls (HCs; n = 20). We performed a functional connectivity analysis seeded in the cortical areas with the highest density of VENs followed by fuzzy clustering. The alterations found in the SZ group were correlated with psychopathological, cognitive, and functioning variables. We found a frontotemporal network that was shared by four clusters overlapping with the salience, superior-frontal, orbitofrontal, and central executive networks. Differences between the HC and SZ groups emerged only in the salience network. The functional connectivity of the right anterior insula and ventral tegmental area within this network were negatively correlated with experiential negative symptoms and positively correlated with functioning. This study provides some evidence to show that in vivo, VEN-enriched cortical areas are associated with an altered resting-state brain activity in people with SZ.

Laminar-Specific Alterations in Calbindin-Positive Boutons in the Prefrontal Cortex of Subjects With Schizophrenia

BackgroundCognitive deficits in schizophrenia are associated with altered GABA (gamma-aminobutyric acid) neurotransmission in the prefrontal cortex (PFC). GABA neurotransmission requires GABA synthesis by 2 isoforms of glutamic acid decarboxylase (GAD65 and GAD67) and packaging by the vesicular GABA transporter (vGAT). Current postmortem findings suggest that GAD67 messenger RNA is lower in a subset of the calbindin-expressing (CB+) class of GABA neurons in schizophrenia. Hence, we assessed if CB+ GABA neuron boutons are affected in schizophrenia. MethodsFor 20 matched pairs of subjects with schizophrenia and unaffected comparison subjects, PFC tissue sections were immunolabeled for vGAT, CB, GAD67, and GAD65. The density of CB+ GABA boutons and levels of the 4 proteins per bouton were quantified. ResultsSome CB+ GABA boutons contained both GAD65 and GAD67 (GAD65+/GAD67+), whereas others contained only GAD65 (GAD65+) or GAD67 (GAD67+). In schizophrenia, vGAT+/CB+/GAD65+/GAD67+ bouton density was not altered, vGAT+/CB+/GAD65+ bouton density was 86% higher in layers 2/superficial 3 (L2/3s), and vGAT+/CB+/GAD67+ bouton density was 36% lower in L5-6. Bouton GAD levels were differentially altered across bouton types and layers. In schizophrenia, the sum of GAD65 and GAD67 levels in vGAT+/CB+/GAD65+/GAD67+ boutons was 36% lower in L6, GAD65 levels were 51% higher in vGAT+/CB+/GAD65+ boutons in L2, and GAD67 levels in vGAT+/CB+/GAD67+ boutons were 30% to 46% lower in L2/3s-6. ConclusionsThese findings indicate that schizophrenia-associated alterations in the strength of inhibition from CB+ GABA neurons in the PFC differ across cortical layers and bouton classes, suggesting complex contributions to PFC dysfunction and cognitive impairments in schizophrenia.

Transcriptional profile of pyramidal neurons in chronic schizophrenia reveals lamina-specific dysfunction of neuronal immunity.

While the pathophysiology of schizophrenia has been extensively investigated using homogenized postmortem brain samples, few studies have examined changes in brain samples with techniques that may attribute perturbations to specific cell types. To fill this gap, we performed microarray assays on mRNA isolated from anterior cingulate cortex (ACC) superficial and deep pyramidal neurons from 12 schizophrenia and 12 control subjects using laser capture microdissection. Among all the annotated genes, we identified 134 significantly increased and 130 decreased genes in superficial pyramidal neurons, while 93 significantly increased and 101 decreased genes were found in deep pyramidal neurons, in schizophrenia compared to control subjects. In these differentially expressed genes, we detected lamina-specific changes of 55 and 31 genes in superficial and deep neurons in schizophrenia, respectively. Gene set enrichment analysis (GSEA) was applied to the entire pre-ranked differential expression gene lists to gain a complete pathway analysis throughout all annotated genes. Our analysis revealed over-represented groups of gene sets in schizophrenia, particularly in immunity and synapse related pathways, suggesting the disruption of these pathways plays an important role in schizophrenia. We also detected other pathways previously demonstrated in schizophrenia pathophysiology, including cytokine and chemotaxis, post-synaptic signaling, and glutamatergic synapses. In addition, we observed several novel pathways, including ubiquitin-independent protein catabolic process. Considering the effects of antipsychotic treatment on gene expression, we applied a novel bioinformatics approach to compare our differential expression gene profiles with 51 antipsychotic treatment datasets, demonstrating that our results were not influenced by antipsychotic treatment. Taken together, we found pyramidal neuron-specific changes in neuronal immunity, synaptic dysfunction, and olfactory dysregulation in schizophrenia, providing new insights for the cell-subtype specific pathophysiology of chronic schizophrenia.

Dendritic Spine Differences in iPSC-Derived Cortical Neurons in Schizophrenia

Postmortem studies of schizophrenia show well-replicated neuronal differences in the prefrontal cortex, with decreased dendritic spine density in layer III cortical pyramidal neurons but not in layer V/VI neurons.

Prefrontal Cortical Alterations of Actin Regulation and Energy Production in Layer 3 Pyramidal Neurons in Schizophrenia

Working memory, the ability to transiently maintain and manipulate a limited amount of information to guide thought or behavior, is impaired in schizophrenia. This impairment has been suggested to stem from hypoactive glutamatergic pyramidal neurons in layer 3 (L3PNs) of the dorsolateral prefrontal cortex (DLPFC). In schizophrenia, L3PNs exhibit morphological abnormalities such as smaller somal sizes, shorter dendritic arbors, and fewer dendritic spines, features that are all regulated by actin dynamics.

Betaine Ameliorates Schizophrenic Traits by Functionally Compensating KIF3-Based CRMP2 Transport

Neurons in schizophrenia (SCZ) brains tend to undergo gross morphological changes, but its molecular mechanism is still largely elusive. Using Kif3b+/- mice as a SCZ model, here we show that high betaine diet can significantly remedy their schizophrenic traits in neuronal morphogenesis and social behavior. We identified significant reduction and restoration by betaine of lamellipodial dynamics in developing Kif3b+/- neurons as a cause of neurite hyperbranching, according to a local deficiency of collapsin response mediator protein 2 (CRMP2) transported by the KIF3 motor. Betaine administration significantly decreased the CRMP2 carbonylation, which enhanced its F-actin bundling activity necessary for proper lamellipodial dynamics and peripheral microtubule exclusion, and thus may functionally compensate the KIF3 deficiency. Because KIF3 expression levels tended to be downregulated in human prefrontal cortex of postmortem SCZ patient brains, this mechanism may also take part in human SCZ pathogenesis, which we propose will be remedied by betaine administration.

Transcriptional Profile of Pyramidal Neurons in Chronic Schizophrenia Reveals Lamina-Specific Dysfunction of Neuronal Immunity

Abstract While the pathophysiology of schizophrenia has been extensively investigated using homogenized postmortem brain samples, few studies have examined changes in brain samples with techniques that may attribute perturbations to specific cell types. To fill this gap, we performed microarray assays on mRNA isolated from anterior cingulate cortex (ACC) superficial and deep pyramidal neurons from 12 schizophrenia and 12 control subjects using laser capture microdissection. Among all the annotated genes, we identified 134 significantly increased and 130 decreased genes in superficial pyramidal neurons, while 93 significantly increased and 101 decreased genes were found in deep pyramidal neurons, in schizophrenia compared to control subjects. In these differentially expressed genes, we detected lamina-specific changes of 55 and 31 genes in superficial and deep neurons in schizophrenia, respectively. Gene set enrichment analysis (GSEA) was applied to the entire pre-ranked differential expression gene lists to gain a complete pathway analysis throughout all annotated genes. Our analysis revealed over-represented groups of gene sets in schizophrenia, particularly in immunity and synapse related pathways in pyramidal neurons, suggesting the disruption of these pathways plays an important role in schizophrenia. We also detected pathways previously demonstrated in schizophrenia pathophysiology, including cytokine and chemotaxis, post-synaptic signaling, and glutamatergic synapses. In addition, we observed several novel pathways, including ubiquitin-independent protein catabolic process. By comparing our differential expression gene profiles with 51 antipsychotic treatment datasets, we demonstrated that our results were not influenced by antipsychotic treatment of our subjects. Taken together, we found pyramidal neuron-specific changes in neuronal immunity, synaptic dysfunction, and olfactory dysregulation in schizophrenia, providing new insights for the cell-subtype specific pathophysiology of chronic schizophrenia.

Comparative Analysis of Autism Spectrum Disorders and Schizophrenia in Childhood

Several problems arise during the diagnosis of children with autism spectrum disorders (ASD) or children with child schizophrenia due to the similarity of mechanisms and manifestations of these two types of pathology. In this paper we analyzed the literature data to determine the differences in the diagnosis of ASD and schizophrenia. This issue is important for understanding the fundamental patterns of these two types of disorders during child development and for appropriate correction and rehabilitation procedures. We identified some consistent indicators of bioelectric activity typical of schizophrenic and autistic types of development. The indicators of the schizophrenic type include “hypofrontality” (i.e., a large representation of slow rhythms in frontal areas) and dextral dominance of the α rhythm. The indicators of the autistic type include the maximum reduction of the α rhythm accompanied by an increase in the γ rhythm representation, changes in synchronization of slow waves during cognitive task performance, maximal activation of visual and acoustical areas of the cortex (which may be associated with abnormally low thresholds in autistic children). Verbal function is more affected in ASD than in schizophrenia; the recognition of mental condition of other people is more disordered. Significant differences between ASD and schizophrenia were detected in comparing attention function disturbances. Marked and vigorous changes in the mirror neuron system were observed in ASD; data on mirror neurons in schizophrenia are contradictory.

(Micro)Glia as Effectors of Cortical Volume Loss in Schizophrenia.

Contrary to the notion that neurology but not psychiatry is the domain of disorders evincing structural brain alterations, it is now clear that there are subtle but consistent neuropathological changes in schizophrenia. These range from increases in ventricular size to dystrophic changes in dendritic spines. A decrease in dendritic spine density in the prefrontal cortex (PFC) is among the most replicated of postmortem structural findings in schizophrenia. Examination of the mechanisms that account for the loss of dendritic spines has in large part focused on genes and molecules that regulate neuronal structure. But the simple question of what is the effector of spine loss, ie, where do the lost spines go, is unanswered. Recent data on glial cells suggest that microglia (MG), and perhaps astrocytes, play an important physiological role in synaptic remodeling of neurons during development. Synapses are added to the dendrites of pyramidal cells during the maturation of these neurons; excess synapses are subsequently phagocytosed by MG. In the PFC, this occurs during adolescence, when certain symptoms of schizophrenia emerge. This brief review discusses recent advances in our understanding of MG function and how these non-neuronal cells lead to structural changes in neurons in schizophrenia.

F198. EFFECTS OF CANNABINOIDS ON A HUMAN OLIGODENDROCYTE CULTURE: IMPLICATIONS FOR SCHIZOPHRENIA

BackgroundPreclinical and clinical studies have suggested the involvement of the endocannabinoid system in schizophrenia pathobiology. In addition, in vitro studies have shown the molecular pathways and biological processes associated with cannabinoids’ effects in some cell types, such as glial cell cultures. Thus, the effects of cannabinoid drugs on these cells may contribute to our knowledge about the pathobiology of schizophrenia. Specifically, oligodendrocytes are associated with white matter deficits in schizophrenia. The modulation of their function, survival, and differentiation can result in new approaches to treat schizophrenia’s white matter-associated deficits. Here we have investigated the effects of cannabidiol (CBD) on a human oligodendrocyte culture (MO3.13). In another experiment, we pretreated the MO3.13 with MK801, an in vitro model of study schizophrenia proposed by our group, in terms of protein expression.MethodsMO3.13 oligodendrocytes were treated with CBD (1µM), or MK801 (50 µM) followed by CBD (1 µM). After 8 hours, proteins were extracted from these cells, digested, and processed in a state-of-the-art LC-MS/MS system. Quantitative proteomics approaches were then employed in a label-free fashion. Differentially expressed proteins were analyzed using systems biology in silico tools.ResultsAnalyses identified that several proteins were up- or down-regulated in response to CBD treatment. These proteins were analyzed in terms of biological processes, pathways, and functions. CBD affected the expression of 136 proteins. Some proteins such as the transient receptor potential channel, microtubule-associated proteins, Rho GTPase activating proteins (21 and 23), and the calcium channel, voltage-dependent T type alpha 1H subunit, among others possibly involved in myelination process, were increased by CBD. Additionally, the MK801-treatment decreased proteins of cytoskeleton, microtubule and RHO GTPases activate KTN1. MK801 also increased proteins involved in glycolysis and eukaryotic translation initiation and CBD attenuated these changes.DiscussionStudies have shown the effects of CBD on the treatment of schizophrenia; but the mechanisms involved in its antipsychotic properties are not fully understood. Herein, we observed that CBD modulated the expression of proteins that can be implicated in schizophrenia pathobiology. For instance, MAPs functions are related to cytoskeleton organization, differentiation, and migration of oligodendrocytes. Studies have shown a decrease of MAPs in schizophrenia patients; thus, increasing MAP2 and MAP4 by CBD may be an interesting mechanism to treat and prevent cytoskeleton impairments in oligodendrocytes and neurons in schizophrenia. Moreover, CBD increased the voltage gated channel that is involved in cannabinoid retrograde signaling and glutamate and GABAergic neurotransmission. CACNA1H modulates Ca2+ levels and the synaptic vesicle cycle. To note, we also found effects of CBD on pathways and biological processes involved with schizophrenia pathobiology, such as glucose metabolism, axon guidance, and inflammation mediated by cytokine signaling. In relation to MK801-treatement, we observed that affected proteins involved in glycolysis and CBD attenuated this change, like antipsychotics (as demonstrated in Cassoli et al., 2016). Moreover, MK801-treatment affected the RHO GTPases family that has been implicated in schizophrenia, and CBD increased these proteins. In summary, these proteomic findings may provide an integrated picture of the role of endocannabinoid signaling in oligodendrocyte cells and possible implications for schizophrenia’s pathobiology.

Chapter 13 - Collecting, storing, and mining research data in a brain bank

The Stanley Medical Research Institute Brain Collection distributes samples from specified cohorts that contain demographically matched groups of subjects with mental illnesses such as schizophrenia, bipolar disorder, and major depression, as well as unaffected controls. The groups are matched by age, sex, race, postmortem interval, pH, side of brain, and mRNA quality. The samples are distributed coded so that all data must be returned in order to obtain the demographic information. The database contains more than 5000 individual data sets, as well as data from high-throughput microarray, sequencing, and proteomic studies. While most data were generated from the frontal cortex and hippocampus, the cerebellum has the most data sets that differ significantly between diagnostic groups and controls. The database contains interactive features and statistical tools that enable online data mining and real-time data analysis. The decrease in density of parvalbumin-positive neurons in schizophrenia, one of the most replicated findings in the field, is used to illustrate features of the brain bank. We describe how this finding can be replicated and validated in this database. We also show how the density of parvalbumin-positive neurons is correlated with markers of immune activation in the neuropathology data sets, how it is correlated with immune-related genes in a microarray data set, and how it is associated with a single-nucleotide polymorphism in the immune complement system.

Insulin-regulated aminopeptidase immunoreactivity is abundantly present in human hypothalamus and posterior pituitary gland, with reduced expression in paraventricular and suprachiasmatic neurons in chronic schizophrenia.

The vasopressin- and oxytocin-degrading enzyme insulin-regulated aminopeptidase (IRAP) is expressed in various organs including the brain. However, knowledge about its presence in human hypothalamus is fragmentary. Functionally, for a number of reasons (genetic linkage, hydrolysis of oxytocin and vasopressin, its role as angiotensin IV receptor in learning and memory and others) IRAP might play a role in schizophrenia. We studied the regional and cellular localization of IRAP in normal human brain with special emphasis on the hypothalamus and determined numerical densities of IRAP-expressing cells in the paraventricular, supraoptic and suprachiasmatic nuclei in schizophrenia patients and controls. By using immunohistochemistry and Western blot analysis, IRAP was immunolocalized in postmortem human brains. Cell countings were performed to estimate numbers and numerical densities of IRAP immunoreactive hypothalamic neurons in schizophrenia patients and control cases. Shape, size and regional distribution of IRAP-expressing cells, as well the lack of co-localization with the glia marker glutamine synthetase, show that IRAP is expressed in neurons. IRAP immunoreactive cells were observed in the hippocampal formation, cerebral cortex, thalamus, amygdala and, abundantly, hypothalamus. Double labeling experiments (IRAP and oxytocin/neurophysin 1, IRAP with vasopressin/neurophysin 2) revealed that IRAP is present in oxytocinergic and in vasopressinergic neurons. In schizophrenia patients, the numerical density of IRAP-expressing neurons in the paraventricular and the suprachiasmatic nuclei is significantly reduced, which might be associated with the reduction in neurophysin-containing neurons in these nuclei in schizophrenia. The pathophysiological role of lowered hypothalamic IRAP expression in schizophrenia remains to be established.