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 overrepresented 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, postsynaptic 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.

mGluR5 hypofunction is integral to glutamatergic dysregulation in schizophrenia.

Multiple lines of evidence point to glutamatergic signaling in the postsynaptic density (PSD) as a pathophysiologic mechanism in schizophrenia. Integral to PSD glutamatergic signaling is reciprocal interplay between GluN and mGluR5 signaling. We examined agonist-induced mGluR5 signaling in the postmortem dorsolateral prefrontal cortex (DLPFC) derived from 17 patients and age-matched and sex-matched controls. The patient group showed a striking reduction in mGluR5 signaling, manifested by decreases in Gq/11 coupling and association with PI3K and Homer compared to controls (p < 0.01 for all). This was accompanied by increases in serine and tyrosine phosphorylation of mGluR5, which can decrease mGluR5 activity via desensitization (p < 0.01). In addition, we find altered protein-protein interaction (PPI) of mGluR5 with RGS4, norbin, Preso 1 and tamalin, which can also attenuate mGluR5 activity. We previously reported molecular underpinnings of GluN hypofunction (decreased GluN2 phosphorylation) and here we show those of reduced mGluR5 signaling in schizophrenia. We find that reduced GluN2 phosphorylation can be precipitated by attenuated mGluR5 activity and that increased mGluR5 phosphorylation can result from decreased GluN function, suggesting a reciprocal interplay between the two pathways in schizophrenia. Interestingly, the patient group showed decreased mGluR5-GluN association (p < 0.01), a mechanistic basis for the reciprocal facilitation. In sum, we present the first direct evidence for mGluR5 hypoactivity, propose a reciprocal interplay between GluN and mGluR5 pathways as integral to glutamatergic dysregulation and suggest protein-protein interactions in mGluR5-GluN complexes as potential targets for intervention in schizophrenia.

Dysregulations of Synaptic Vesicle Trafficking in Schizophrenia.

Schizophrenia is a serious psychiatric illness which is experienced by about 1 % of individuals worldwide and has a debilitating impact on perception, cognition, and social function. Over the years, several models/hypotheses have been developed which link schizophrenia to dysregulations of the dopamine, glutamate, and serotonin receptor pathways. An important segment of these pathways that have been extensively studied for the pathophysiology of schizophrenia is the presynaptic neurotransmitter release mechanism. This set of molecular events is an evolutionarily well-conserved process that involves vesicle recruitment, docking, membrane fusion, and recycling, leading to efficient neurotransmitter delivery at the synapse. Accumulated evidence indicate dysregulation of this mechanism impacting postsynaptic signal transduction via different neurotransmitters in key brain regions implicated in schizophrenia. In recent years, after ground-breaking work that elucidated the operations of this mechanism, research efforts have focused on the alterations in the messenger RNA (mRNA) and protein expression of presynaptic neurotransmitter release molecules in schizophrenia and other neuropsychiatric conditions. In this review article, we present recent evidence from schizophrenia human postmortem studies that key proteins involved in the presynaptic release mechanism are dysregulated in the disorder. We also discuss the potential impact of dysfunctional presynaptic neurotransmitter release on the various neurotransmitter systems implicated in schizophrenia.

Biochemical fractionation and stable isotope dilution liquid chromatography-mass spectrometry for targeted and microdomain-specific protein quantification in human postmortem brain tissue.

Synaptic architecture and its adaptive changes require numerous molecular events that are both highly ordered and complex. A majority of neuropsychiatric illnesses are complex trait disorders, in which multiple etiologic factors converge at the synapse via many signaling pathways. Investigating the protein composition of synaptic microdomains from human patient brain tissues will yield valuable insights into the interactions of risk genes in many disorders. These types of studies in postmortem tissues have been limited by the lack of proper study paradigms. Thus, it is necessary not only to develop strategies to quantify protein and post-translational modifications at the synapse, but also to rigorously validate them for use in postmortem human brain tissues. In this study we describe the development of a liquid chromatography-selected reaction monitoring method, using a stable isotope-labeled neuronal proteome standard prepared from the brain tissue of a stable isotope-labeled mouse, for the multiplexed quantification of target synaptic proteins in mammalian samples. Additionally, we report the use of this method to validate a biochemical approach for the preparation of synaptic microdomain enrichments from human postmortem prefrontal cortex. Our data demonstrate that a targeted mass spectrometry approach with a true neuronal proteome standard facilitates accurate and precise quantification of over 100 synaptic proteins in mammalian samples, with the potential to quantify over 1000 proteins. Using this method, we found that protein enrichments in subcellular fractions prepared from human postmortem brain tissue were strikingly similar to those prepared from fresh mouse brain tissue. These findings demonstrate that biochemical fractionation methods paired with targeted proteomic strategies can be used in human brain tissues, with important implications for the study of neuropsychiatric disease.

Blocking Src-PSD-95 interaction rescues glutamatergic signaling dysregulation in schizophrenia.

The complex and heterogeneous genetic architecture of schizophrenia inspires us to look beyond individual risk genes for therapeutic strategies and target their interactive dynamics and convergence. Postsynaptic NMDA receptor (NMDAR) complexes are a site of such convergence. Src kinase is a molecular hub of NMDAR function, and its protein interaction subnetwork is enriched for risk-genes and altered protein associations in schizophrenia. Previously, Src activity was found to be decreased in post-mortem studies of schizophrenia, contributing to NMDAR hypofunction. PSD-95 suppresses Src via interacting with its SH2 domain. Here, we devised a strategy to suppress the inhibition of Src by PSD-95 via employing a cell penetrating and Src activating PSD-95 inhibitory peptide (TAT-SAPIP). TAT-SAPIP selectively increased post-synaptic Src activity in humans and mice, and enhanced synaptic NMDAR currents in mice. Chronic ICV injection of TAT-SAPIP rescued deficits in trace fear conditioning in Src hypomorphic mice. We propose blockade of the Src-PSD-95 interaction as a proof of concept for the use of interfering peptides as a therapeutic strategy to reverse NMDAR hypofunction in schizophrenia and other illnesses.

HDAC6 regulates glucocorticoid receptor signaling in serotonin pathways with critical impact on stress resilience.

Genetic variations in certain components of the glucocorticoid receptor (GR) chaperone complex have been associated with the development of stress-related affective disorders and individual variability in therapeutic responses to antidepressants. Mechanisms that link GR chaperoning and stress susceptibility are not well understood. Here, we show that the effects of glucocorticoid hormones on socioaffective behaviors are critically regulated via reversible acetylation of Hsp90, a key component of the GR chaperone complex. We provide pharmacological and genetic evidence indicating that the cytoplasmic lysine deacetylase HDAC6 controls Hsp90 acetylation in the brain, and thereby modulates Hsp90-GR protein-protein interactions, as well as hormone- and stress-induced GR translocation, with a critical impact on GR downstream signaling and behavior. Pet1-Cre-driven deletion of HDAC6 in serotonin neurons, the densest HDAC6-expressing cell group in the mouse brain, dramatically reduced acute anxiogenic effects of the glucocorticoid hormone corticosterone in the open-field, elevated plus maze, and social interaction tests. Serotonin-selective depletion of HDAC6 also blocked the expression of social avoidance in mice exposed to chronic social defeat and concurrently prevented the electrophysiological and morphological changes induced, in serotonin neurons, by this murine model of traumatic stress. Together, these results identify HDAC6 inhibition as a potential new strategy for proresilience and antidepressant interventions through regulation of the Hsp90-GR heterocomplex and focal prevention of GR signaling in serotonin pathways. Our data thus uncover an alternate mechanism by which pan-HDAC inhibitors may regulate stress-related behaviors independently of their action on histones.

Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia.

Recent molecular genetics studies implicate neuregulin 1 (NRG1) and its receptor erbB in the pathophysiology of schizophrenia. Among NRG1 receptors, erbB4 is of particular interest because of its crucial roles in neurodevelopment and in the modulation of N-methyl-D-aspartate (NMDA) receptor signaling. Here, using a new postmortem tissue-stimulation approach, we show a marked increase in NRG1-induced activation of erbB4 in the prefrontal cortex in schizophrenia. Levels of NRG1 and erbB4, however, did not differ between schizophrenia and control groups. To evaluate possible causes for this hyperactivation of erbB4 signaling, we examined the association of erbB4 with PSD-95 (postsynaptic density protein of 95 kDa), as this association has been shown to facilitate activation of erbB4. Schizophrenia subjects showed substantial increases in erbB4-PSD-95 interactions. We found that NRG1 stimulation suppresses NMDA receptor activation in the human prefrontal cortex, as previously reported in the rodent cortex. NRG1-induced suppression of NMDA receptor activation was more pronounced in schizophrenia subjects than in controls, consistent with enhanced NRG1-erbB4 signaling seen in this illness. Therefore, these findings suggest that enhanced NRG1 signaling may contribute to NMDA hypofunction in schizophrenia.

Transcriptional profiles in olfactory pathway-associated brain regions of African green monkeys: Associations with age and Alzheimer's disease neuropathology.

Introduction: Olfactory impairment in older individuals is associated with an increased risk of Alzheimer's disease (AD). Characterization of age versus neuropathology-associated changes in the brain olfactory pathway may elucidate processes underlying early AD pathogenesis. Here, we report age versus AD neuropathology-associated differential transcription in four brain regions in the olfactory pathway of 10 female African green monkeys (vervet, Chlorocebus aethiops sabaeus), a well-described model of early AD-like neuropathology. Methods: Transcriptional profiles were determined by microarray in the olfactory bulb (OB), piriform cortex (PC), temporal lobe white matter (WM), and inferior temporal cortex (ITC). Amyloid beta (Aß) plaque load in parietal and temporal cortex was determined by immunohistochemistry, and concentrations of Aß42, Aß40, and norepinephrine in ITC were determined by enzyme-linked immuosorbent assay (ELISA). Transcriptional profiles were compared between middle-aged and old animals, and associations with AD-relevant neuropathological measures were determined. Results: Transcriptional profiles varied by brain region and age group. Expression levels of TRO and RNU4-1 were significantly lower in all four regions in the older group. An additional 29 genes were differentially expressed by age in three of four regions. Analyses of a combined expression data set of all four regions identified 77 differentially expressed genes (DEGs) by age group. Among these DEGs, older subjects had elevated levels of CTSB , EBAG9, LAMTOR3, and MRPL17, and lower levels of COMMD10 and TYW1B. A subset of these DEGs was associated with neuropathology biomarkers. Notably, CTSB was positively correlated with Aß plaque counts, Aß42:Aß40 ratios, and norepinephrine levels in all brain regions. Discussion: These data demonstrate age differences in gene expression in olfaction-associated brain regions. Biological processes exhibiting age-related enrichment included the regulation of cell death, vascular function, mitochondrial function, and proteostasis. A subset of DEGs was specifically associated with AD phenotypes. These may represent promising targets for future mechanistic investigations and perhaps therapeutic intervention.

Chromatin domain alterations linked to 3D genome organization in a large cohort of schizophrenia and bipolar disorder brains.

Chromosomal organization, scaling from the 147-base pair (bp) nucleosome to megabase-ranging domains encompassing multiple transcriptional units, including heritability loci for psychiatric traits, remains largely unexplored in the human brain. In this study, we constructed promoter- and enhancer-enriched nucleosomal histone modification landscapes for adult prefrontal cortex from H3-lysine 27 acetylation and H3-lysine 4 trimethylation profiles, generated from 388 controls and 351 individuals diagnosed with schizophrenia (SCZ) or bipolar disorder (BD) (n = 739). We mapped thousands of cis-regulatory domains (CRDs), revealing fine-grained, 104-106-bp chromosomal organization, firmly integrated into Hi-C topologically associating domain stratification by open/repressive chromosomal environments and nuclear topography. Large clusters of hyper-acetylated CRDs were enriched for SCZ heritability, with prominent representation of regulatory sequences governing fetal development and glutamatergic neuron signaling. Therefore, SCZ and BD brains show coordinated dysregulation of risk-associated regulatory sequences assembled into kilobase- to megabase-scaling chromosomal domains.

Maintenance of Wellness in Patients With Obsessive-Compulsive Disorder Who Discontinue Medication After Exposure/Response Prevention Augmentation: A Randomized Clinical Trial.

IMPORTANCE: Serotonin reuptake inhibitors (SRIs) are the only medications approved for obsessive-compulsive disorder (OCD), yet most patients taking SRIs exhibit significant symptoms. Adding exposure/response prevention (EX/RP) therapy improves symptoms, but it is unknown whether patients maintain wellness after discontinuing SRIs. OBJECTIVE: To assess whether patients with OCD who are taking SRIs and have attained wellness after EX/RP augmentation can discontinue their SRI with noninferior outcomes compared with those who continue their SRI therapy. DESIGN, SETTING, AND PARTICIPANTS: A 24-week, double-blind, randomized clinical trial was performed from May 3, 2013, to June 25, 2018. The trial took place at US academic medical centers. Participants included 137 adults with a principal diagnosis of OCD (≥1 year) who were taking an SRI (≥12 weeks), had at least moderate symptoms (defined as Yale-Brown Obsessive-Compulsive Scale [Y-BOCS] score ≥18 points), and received as many as 25 sessions of EX/RP therapy. Those who attained wellness (Y-BOCS score ≤14 points; 103 patients [75.2%]) were study eligible. Data were analyzed from June 29, 2019, to October 2, 2021. INTERVENTION: Participants were randomly assigned either to receive taper to placebo (taper group) or to continue their SRI (continuation group) and monitored for 24 weeks. MAIN OUTCOME AND MEASURES: The Y-BOCS score (range, 0-40 points) was the primary outcome; the Hamilton Depression Rating Scale (HDRS; range, 0-52 points) and the Quality-of-Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF; range, 0%-100%) scores were secondary outcomes. Outcomes were assessed at 8 time points by independent evaluators who were blinded to randomization. The taper regimen was hypothesized to be noninferior to continuation at 24 weeks using a 1-sided α value of .05. RESULTS: A total of 101 patients (mean [SD] age, 31.0 [11.2] years; 55 women [54.5%]) participated in the trial: 51 patients (50.5%) in the taper group and 50 patients (49.5%) in the continuation group. At 24 weeks, patients in the taper group had noninferior results compared with patients in the continuation group (mean [SD] Y-BOCS score: taper group, 11.47 [6.56] points; continuation group: 11.51 [5.97] points; difference, -0.04 points; 1-sided 95% CI, -∞ to 2.09 points [below the noninferiority margin of 3.0 points]; mean [SD] HDRS score: taper group, 5.69 [3.84] points; continuation group, 4.61 [3.46] points; difference, 1.08 points; 1-sided 95% CI, -∞ to 2.28 points [below the noninferiority margin of 2.5 points]; mean [SD] Q-LES-Q-SF score: taper group, 68.01% [15.28%]; continuation group, 70.01% [15.59%]; difference, 2.00%; 1-sided 95% CI, -∞ to 6.83 [below the noninferiority margin of 7.75]). However, the taper group had higher rates of clinical worsening (23 of 51 [45%] vs 12 of 50 [24%]; P = .04). CONCLUSIONS AND RELEVANCE: Results of this randomized clinical trial show that patients with OCD who achieve wellness after EX/RP therapy could, on average, discontinue their SRI with noninferior outcomes compared with those who continued their SRI. Those who tapered the SRI had higher clinical worsening rates. Future research should evaluate if SRI half-life alters these rates. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01686087.

Dysbindin-1 in dorsolateral prefrontal cortex of schizophrenia cases is reduced in an isoform-specific manner unrelated to dysbindin-1 mRNA expression.

DTNBP1 (dystrobrevin binding protein 1) remains a top candidate gene in schizophrenia. Reduced expression of this gene and of its encoded protein, dysbindin-1, have been reported in the brains of schizophrenia cases. It has not been established, however, if the protein reductions encompass all dysbindin-1 isoforms or if they are associated with decreased DTNBP1 gene expression. Using a matched pairs design in which each of 28 Caucasian schizophrenia cases was matched in age and sex to a normal Caucasian control, Western blotting of whole-tissue lysates of dorsolateral prefrontal cortex (DLPFC) revealed significant reductions in dysbindin-1C (but not in dysbindin-1A or -1B) in schizophrenia (P = 0.022). These reductions occurred without any significant change in levels of the encoding transcript in the same tissue samples and in the absence of the only DTNBP1 risk haplotype for schizophrenia reported in the USA. Indeed, no significant correlations were found between case-control differences in any dysbindin-1 isoform and the case-control differences in its encoding mRNA. Consequently, the mean 60% decrease in dysbindin-1C observed in 71% of our case-control pairs appears to reflect abnormalities in mRNA translation and/or processes promoting dysbindin-1C degradation (e.g. oxidative stress, phosphorylation and/or ubiquitination). Given the predominantly post-synaptic localization of dysbindin-1C and known post-synaptic effects of dysbindin-1 reductions in the rodent equivalent of the DLPFC, the present findings suggest that decreased dysbindin-1C in the DLPFC may contribute to the cognitive deficits of schizophrenia by promoting NMDA receptor hypofunction in fast-spiking interneurons.

Maximizing remission from cognitive-behavioral therapy in medicated adults with obsessive-compulsive disorder.

Practice guidelines for adults with obsessive-compulsive disorder (OCD) recommend augmenting serotonin reuptake inhibitors (SRIs) with exposure and ritual prevention (EX/RP). However, fewer than half of patients remit after a standard 17-session EX/RP course. We studied whether extending the course increased overall remission rates and which patient factors predicted remission. Participants were 137 adults with clinically significant OCD (Yale-Brown Obsessive Compulsive Scale [Y-BOCS] score ≥18) despite an adequate SRI trial (≥12 weeks). Continuing their SRI, patients received 17 sessions of twice-weekly EX/RP (standard course). Patients who did not remit (Y-BOCS ≤12) received up to 8 additional sessions (extended course). Of 137 entrants, 123 completed treatment: 49 (35.8%) remitted with the standard course and another 46 (33.6%) with the extended course. Poorer patient homework adherence, more Obsessive-Compulsive Personality Disorder (OCPD) traits, and the Brain-Derived Neurotrophic Factor (BDNF) Val66MET genotype were associated with lower odds of standard course remission. Only homework adherence differentiated non-remitters from extended course remitters. Extending the EX/RP course from 17 to 25 sessions enabled many (69.3%) OCD patients on SRIs to achieve remission. Although behavioral (patient homework adherence), psychological (OCPD traits), and biological (BDNF genotype) factors influenced odds of EX/RP remission, homework adherence was the most potent patient factor overall.

The proteome and its dynamics: A missing piece for integrative multi-omics in schizophrenia.

The complex and heterogeneous pathophysiology of schizophrenia can be deconstructed by integration of large-scale datasets encompassing genes through behavioral phenotypes. Genome-wide datasets are now available for genetic, epigenetic and transcriptomic variations in schizophrenia, which are then analyzed by newly devised systems biology algorithms. A missing piece, however, is the inclusion of information on the proteome and its dynamics in schizophrenia. Proteomics has lagged behind omics of the genome, transcriptome and epigenome since analytic platforms were relatively less robust for proteins. There has been remarkable progress, however, in the instrumentation of liquid chromatography (LC) and mass spectrometry (MS) (LCMS), experimental paradigms and bioinformatics of the proteome. Here, we present a summary of methodological innovations of recent years in MS based proteomics and the power of new generation proteomics, review proteomics studies that have been conducted in schizophrenia to date, and propose how such data can be analyzed and integrated with other omics results. The function of a protein is determined by multiple molecular properties, i.e., subcellular localization, posttranslational modification (PTMs) and protein-protein interactions (PPIs). Incorporation of these properties poses additional challenges in proteomics and their integration with other omics; yet is a critical next step to close the loop of multi-omics integration. In sum, the recent advent of high-throughput proteome characterization technologies and novel mathematical approaches enable us to incorporate functional properties of the proteome to offer a comprehensive multi-omics based understanding of schizophrenia pathophysiology.

Transcriptional corepressor SIN3A regulates hippocampal synaptic plasticity via Homer1/mGluR5 signaling.

Long-term memory depends on the control of activity-dependent neuronal gene expression, which is regulated by epigenetic modifications. The epigenetic modification of histones is orchestrated by the opposing activities of 2 classes of regulatory complexes: permissive coactivators and silencing corepressors. Much work has focused on coactivator complexes, but little is known about the corepressor complexes that suppress the expression of plasticity-related genes. Here, we define a critical role for the corepressor SIN3A in memory and synaptic plasticity, showing that postnatal neuronal deletion of Sin3a enhances hippocampal long-term potentiation and long-term contextual fear memory. SIN3A regulates the expression of genes encoding proteins in the postsynaptic density. Loss of SIN3A increases expression of the synaptic scaffold Homer1, alters the metabotropic glutamate receptor 1α (mGluR1α) and mGluR5 dependence of long-term potentiation, and increases activation of ERK in the hippocampus after learning. Our studies define a critical role for corepressors in modulating neural plasticity and memory consolidation and reveal that Homer1/mGluR signaling pathways may be central molecular mechanisms for memory enhancement.

Novel environment and GABA agonists alter event-related potentials in N-methyl-D-aspartate NR1 hypomorphic and wild-type mice.

Clinical and experimental data suggest dysregulation of N-methyl-d-aspartate receptor (NMDAR)-mediated glutamatergic pathways in schizophrenia. The interaction between NMDAR-mediated abnormalities and the response to novel environment has not been studied. Mice expressing 5 to 10% of normal N-methyl-d-aspartate receptor subunit 1 (NR1) subunits [NR1(neo)(-/-)] were compared with wild-type littermates for positive deflection at 20 ms (P20) and negative deflection at 40 ms (N40) auditory event-related potentials (ERPs). Groups were tested for habituation within and across five testing sessions, with novel environment tested during a sixth session. Subsequently, we examined the effects of a GABA(A) positive allosteric modulator (chlordiazepoxide) and a GABA(B) receptor agonist (baclofen) as potential interventions to normalize aberrant responses. There was a reduction in P20, but not N40 amplitude within each habituation day. Although there was no amplitude or gating change across habituation days, there was a reduction in P20 and N40 amplitude and gating in the novel environment. There was no difference between genotypes for N40. Only NR1(neo)(-/-) mice had reduced P20 in the novel environment. Chlordiazepoxide increased N40 amplitude in wild-type mice, whereas baclofen increased P20 amplitude in NR1(neo)(-/-) mice. As noted in previous publications, the pattern of ERPs in NR1(neo)(-/-) mice does not recapitulate abnormalities in schizophrenia. In addition, reduced NR1 expression does not influence N40 habituation but does affect P20 in a novel environment. Thus, the pattern of P50 (positive deflection at 50 ms) but not N100 (negative deflection at 100 ms) in human studies may relate to subjects' reactions to unfamiliar environments. In addition, NR1 reduction decreased GABA(A) receptor-mediated effects on ERPs while causing increased GABA(B) receptor-mediated effects. Future studies will examine changes in GABA receptor subunits after reductions in NR1 expression.

Smoking-associated squamous metaplasia in olfactory mucosa of patients with chronic rhinosinusitis.

Few studies have examined the induction of squamous metaplasia in human olfactory nasal tissue caused by tobacco use and the implications it may have for olfaction, particularly when there are pre-existing insults, such as chronic rhinosinusitis (CRS). Quantitative histopathological analyses were performed on Alcian blue- and H&E-stained sections of nasal biopsies taken from the upper aspect of the middle turbinate of CRS patients. Chronic rhinosinusitis patients who were current smokers had a predominance of squamous metaplasia in the olfactory sensory epithelium, whereas CRS patients who were nonsmokers and were not exposed to secondhand cigarette smoke had a prevalence of goblet cell hyperplasia. In spite of this difference, the groups did not differ significantly in olfactory threshold sensitivity. The impact of primary cigarette smoke on olfaction and a possible role of squamous metaplasia in preserving olfactory neurogenesis are discussed.

Src deficient mice demonstrate behavioral and electrophysiological alterations relevant to psychiatric and developmental disease.

Much evidence suggests that hypofunction of the N-methyl-d-aspartate glutamate receptor (NMDAR) may contribute broadly towards a subset of molecular, cognitive and behavioral abnormalities common among psychiatric and developmental diseases. However, little is known about the specific molecular changes that lead to NMDAR dysfunction. As such, personalized approaches to remediating NMDAR dysfunction based on a specific etiology remains a challenge. Sarcoma tyrosine kinase (Src) serves as a hub for multiple signaling mechanisms affecting GluN2 phosphorylation and can be disrupted by convergent alterations of various signaling pathways. We recently showed reduced Src signaling in post mortem tissue from schizophrenia patients, despite increased MK-801 binding and NMDA receptor complex expression in the postsynaptic density (PSD). These data suggest that Src dysregulation may be an important underlying mechanism responsible for reduced glutamate signaling. Despite this evidence for a central role of Src in NMDAR signaling, little is known about how reductions in Src activity might regulate phenotypic changes in cognition and behavior. As such, the current study sought to characterize behavioral and electrophysiological phenotypes in mice heterozygous for the Src Acl gene (Src+/- mice). Src+/- mice demonstrated decreased sociability and working memory relative to Src+/+ (WT) mice while no significant differences were seen on locomotive activity and anxiety-related behavior. In relation to WT mice, Src+/- mice showed decreased mid-latency P20 auditory event related potential (aERP) amplitudes, decreased mismatch negativity (MMN) and decreased evoked gamma power, which was only present in males. These data indicate that Src+/- mice are a promising new model to help understand the pathophysiology of these electrophysiological, behavioral and cognitive changes. As such, we propose that Src+/- mice can be used in the future to evaluate potential therapeutic approaches by targeting increased Src activity as a common final pathway for multiple etiologies of SCZ and other diseases characterized by reduced glutamate function.

CommonMind Consortium provides transcriptomic and epigenomic data for Schizophrenia and Bipolar Disorder.

Schizophrenia and bipolar disorder are serious mental illnesses that affect more than 2% of adults. While large-scale genetics studies have identified genomic regions associated with disease risk, less is known about the molecular mechanisms by which risk alleles with small effects lead to schizophrenia and bipolar disorder. In order to fill this gap between genetics and disease phenotype, we have undertaken a multi-cohort genomics study of postmortem brains from controls, individuals with schizophrenia and bipolar disorder. Here we present a public resource of functional genomic data from the dorsolateral prefrontal cortex (DLPFC; Brodmann areas 9 and 46) of 986 individuals from 4 separate brain banks, including 353 diagnosed with schizophrenia and 120 with bipolar disorder. The genomic data include RNA-seq and SNP genotypes on 980 individuals, and ATAC-seq on 269 individuals, of which 264 are a subset of individuals with RNA-seq. We have performed extensive preprocessing and quality control on these data so that the research community can take advantage of this public resource available on the Synapse platform at http://CommonMind.org .

Deficits in docosahexaenoic acid and associated elevations in the metabolism of arachidonic acid and saturated fatty acids in the postmortem orbitofrontal cortex of patients with bipolar disorder.

Previous antemortem and postmortem tissue fatty acid composition studies have observed significant deficits in the omega-3 fatty acid docosahexaenoic acid (DHA, 22:6n-3) in red blood cell (RBC) and postmortem cortical membranes of patients with unipolar depression. In the present study, we determined the fatty acid composition of postmortem orbitofrontal cortex (OFC, Brodmann area 10) of patients with bipolar disorder (n=18) and age-matched normal controls (n=19) by gas chromatography. After correction for multiple comparisons, DHA (-24%), arachidonic acid (-14%), and stearic acid (C18:0) (-4.5%) compositions were significantly lower, and cis-vaccenic acid (18:1n-7) (+12.5%) composition significantly higher, in the OFC of bipolar patients relative to normal controls. Based on metabolite:precursor ratios, significant elevations in arachidonic acid, stearic acid, and palmitic acid conversion/metabolism were observed in the OFC of bipolar patients, and were inversely correlated with DHA composition. Deficits in OFC DHA and arachidonic acid composition, and elevations in arachidonic acid metabolism, were numerically (but not significantly) greater in drug-free bipolar patients relative to patients treated with mood-stabilizer or antipsychotic medications. OFC DHA and arachidonic acid deficits were greater in patients plus normal controls with high vs. low alcohol abuse severity. These results add to a growing body of evidence implicating omega-3 fatty acid deficiency as well as the OFC in the pathoaetiology of bipolar disorder.