Pathophysiology Of Psychiatric Disorders Research Articles

Dysregulation of kappa opioid receptor neuromodulation of lateral habenula synaptic function following a repetitive mild traumatic brain injury

Mild traumatic brain injury (mTBI) increases the risk of affective disorders, anxiety and substance use disorder. The lateral habenula (LHb) plays an important role in pathophysiology of psychiatric disorders. Recently, we demonstrated a causal link between mTBI-induced LHb hyperactivity due to excitation/inhibition (E/I) imbalance and motivational deficits in male mice using a repetitive closed head injury mTBI model. A major neuromodulatory system that is responsive to traumatic brain injuries, influences affective states and also modulates LHb activity is the dynorphin/kappa opioid receptor (Dyn/KOR) system. However, the effects of mTBI on KOR neuromodulation of LHb function are unknown. Here, we first used retrograde tracing in male and female Cre mouse lines and identified several major KOR-expressing and two prominent Dyn-expressing inputs projecting to the mouse LHb, highlighting the medial prefrontal cortex (mPFC) and the ventromedial nucleus of the hypothalamus (VMH) as the main LHb-projecting Dyn inputs that regulate KOR signaling to the LHb. We then functionally evaluated the effects of in vitro KOR modulation of spontaneous synaptic activity within the LHb of male and female sham and mTBI mice at 4 week post-injury. We observed sex-specific differences in spontaneous release of glutamate and GABA from presynaptic terminals onto LHb neurons with higher levels of presynaptic glutamate and GABA release in females compared to male mice. However, KOR effects on the spontaneous E/I ratios and synaptic drive ratio within the LHb did not differ between male and female sham and mTBI mice. KOR activation generally suppressed spontaneous glutamatergic transmission without altering GABAergic transmission, resulting in a significant but sex-similar reduction in net spontaneous E/I and synaptic drive ratios in LHb neurons of sham mice. Following mTBI, while responses to KOR activation at LHb glutamatergic synapses remained intact, LHb GABAergic synapses acquired an additional sensitivity to KOR-mediated inhibition where we observed a reduction in GABA release probability in response to KOR stimulation in LHb neurons of mTBI mice. Further analysis of percent change in spontaneous synaptic ratios induced by KOR activation revealed that independent of sex mTBI switches KOR-driven synaptic inhibition of LHb neurons (normally observed in sham mice) in a subset of mTBI mice toward synaptic excitation resulting in mTBI-induced divergence of KOR actions within the LHb. Overall, we uncovered the sources of major Dyn/KOR-expressing synaptic inputs projecting to the mouse LHb. We demonstrate that an engagement of intra-LHb Dyn/KOR signaling provides a global KOR-driven synaptic inhibition within the mouse LHb independent of sex. The additional engagement of KOR-mediated action on LHb GABAergic transmission by mTBI could contribute to the E/I imbalance after mTBI, with Dyn/KOR signaling serving as a disinhibitory mechanism for LHb neurons of a subset of mTBI mice.

Effects of antidepressant and antipsychotic medication on peripheral brain-derived neurotrophic factor concentration: Systematic review and meta-analysis

Brain-derived neurotrophic factor (BDNF) is an important regulatory protein in the pathophysiology of psychiatric disorders. Several studies have reported the relationship between peripheral BDNF concentrations and the use of psychoactive drugs. However, the results remain controversial. This study aimed to evaluate the effects of psychoactive drugs on BDNF concentrations and to explore the association between changes in BDNF concentrations and improvements in clinical scores. A systematic review and meta-analysis were conducted. Six electronic databases, including PubMed, Scopus, Medline, Web of Science, Google Scholar and Science Direct, were searched. Changes in BDNF concentrations were compared before and after psychoactive treatment, using the standardized mean difference (SMD) and 95 % confidence interval (95 % CI). Twenty-three studies were included. A significant increase in serum BDNF concentrations was observed after treatment with antipsychotics (SMD=0.43; 95 %CI: 0.26, 0.60) and antidepressants (SMD=0.49; 95 %CI: 0.23, 0.74). However, the plasma BDNF concentration was not affected by antidepressant and antipsychotic medication. Although an improvement in clinical scores was observed after treatment, no significant association was observed between changes in BDNF concentrations and the changes in the Positive and Negative Syndrome Scale (PANSS) and the Hamilton Depression Rating Scale (HAM-D) scores. In conclusion, antidepressants and antipsychotics increase serum BDNF concentrations.

Circulating Cell-Free Mitochondrial DNA and Depressive Symptoms Among Low-Active Adults Who Smoke.

Mitochondrial dysfunction is implicated in the pathophysiology of psychiatric disorders. Levels of circulating cell-free mitochondrial DNA (cf-mtDNA) are observed to be altered in depression. However, the few studies that have measured cf-mtDNA in depression have reported conflicting findings. This study examined cf-mtDNA and depressive symptoms in low-active adults who smoke. Participants were adults 18 to 65 years old ( N = 109; 76% female) with low baseline physical activity and depressive symptoms recruited for a smoking cessation study. Self-report measures assessed depression severity, positive and negative affect, and behavioral activation. Blood was collected and analyzed for cf-mtDNA. Relationships between depressive symptoms and cf-mtDNA were examined with correlations and linear regression. Levels of cf-mtDNA were associated with categorically defined depression (Center for Epidemiologic Studies Depression Scale score >15), lower positive affect, and decreased behavioral activation ( p < .05). Relationships remained significant after adjustment for age, sex, and nicotine dependence. In a linear regression model including all depressive symptom measures as predictors, Center for Epidemiologic Studies Depression Scale group and lower positive affect remained significant. This work suggests that mitochondrial changes are associated with depressive symptoms in low-active adults who smoke. Higher levels of cf-mtDNA in association with depression and with lower positive affect and decreased behavioral activation are consistent with a possible role for mitochondrial function in depressive symptoms.

Psychiatric disorders and brain white matter exhibit genetic overlap implicating developmental and neural cell biology.

Improved understanding of the shared genetic architecture between psychiatric disorders and brain white matter may provide mechanistic insights for observed phenotypic associations. Our objective is to characterize the shared genetic architecture of bipolar disorder (BD), major depression (MD), and schizophrenia (SZ) with white matter fractional anisotropy (FA) and identify shared genetic loci to uncover biological underpinnings. We used genome-wide association study (GWAS) summary statistics for BD (n = 413,466), MD (n = 420,359), SZ (n = 320,404), and white matter FA (n = 33,292) to uncover the genetic architecture (i.e., polygenicity and discoverability) of each phenotype and their genetic overlap (i.e., genetic correlations, overlapping trait-influencing variants, and shared loci). This revealed that BD, MD, and SZ are at least 7-times more polygenic and less genetically discoverable than average FA. Even in the presence of weak genetic correlations (range = -0.05 to -0.09), average FA shared an estimated 42.5%, 43.0%, and 90.7% of trait-influencing variants as well as 12, 4, and 28 shared loci with BD, MD, and SZ, respectively. Shared variants were mapped to genes and tested for enrichment among gene-sets which implicated neurodevelopmental expression, neural cell types, myelin, and cell adhesion molecules. For BD and SZ, case vs control tract-level differences in FA associated with genetic correlations between those same tracts and the respective disorder (rBD = 0.83, p = 4.99e-7 and rSZ = 0.65, p = 5.79e-4). Genetic overlap at the tract-level was consistent with average FA results. Overall, these findings suggest a genetic basis for the involvement of brain white matter aberrations in the pathophysiology of psychiatric disorders.

A Precision Medicine Approach to the Treatment of Psychiatric Disorders

Due to a lack of clarity about the pathophysiology of psychiatric disorders, short and long-term treatment outcomes continue to be very inconsistent, and the prescribing of multiple medications that can have unpredictable, conflicting, and sometimes paradoxical effects continues to be more the rule than the exception in modern psychiatric practice. Dosing is also an issue, as standard doses of psychotropic drugs are often too high, thus causing some patients to incur unnecessary side effects, which in turn can lead to poor compliance or even discontinuation of treatment. Worse yet, these negative outcomes can cause disappointed patients to dissuade other would-be patients from seeking treatment. Recognizing these concerns and the fact that most persons with mental illness never seek treatment to begin with, the need for greater precision and fewer side effects in the prescribing of psychotropic drugs cannot be overstated. Based on an emerging hypothesis on the pathophysiology of psychiatric disorders, this article will discuss a promising new approach to psychopharmacotherapy that has the potential to simplify drug selection, reduce dosing requirements, and minimize side effects. By targeting the core physiological abnormality in psychiatric disorders, the use of medications that have unpredictable, conflicting, and sometimes paradoxical effects can be minimized, and the lowest doses of the most appropriate drugs can be used to achieve faster, more consistent, and more enduring therapeutic effects in a group of disorders that are now considered to be a public health crisis.

Identification of epigenetically active L1 promoters in the human brain and their relationship with psychiatric disorders

Long interspersed nuclear element-1 (LINE-1, L1) affects the transcriptome landscape in multiple ways. Promoter activity within its 5’UTR plays a critical role in regulating diverse L1 activities. However, the epigenetic status of L1 promoters in adult brain cells and their relationship with psychiatric disorders remain poorly understood. Here, we examined DNA methylation and hydroxymethylation of the full-length L1s in neurons and nonneurons and identified “epigenetically active” L1s. Notably, some of epigenetically active L1s were retrotransposition competent, which even had chimeric transcripts from the antisense promoters at their 5’UTRs. We also identified differentially methylated L1s in the prefrontal cortices of patients with psychiatric disorders. In nonneurons of bipolar disorder patients, one L1 was significantly hypomethylated and showed an inverse correlation with the expression level of the overlapping gene NREP. Finally, we observed that altered DNA methylation levels of L1 in patients with psychiatric disorders were not affected by the surrounding genomic regions but originated from the L1 sequences. These results suggested that altered epigenetic regulation of the L1 5’UTR in the brain was involved in the pathophysiology of psychiatric disorders.

The expression of agmatinase manipulates the affective state of rats subjected to chronic restraint stress

Agmatine is an endogenous polyamine produced from l-arginine and degraded by agmatinase (AGMAT). Studies in humans and animals have shown that agmatine has neuroprotective, anxiolytic, and antidepressant-like actions. However, little is known about the role of AGMAT in the action of agmatine or in the pathophysiology of psychiatric disorders. Therefore, this study aimed to investigate the role of AGMAT in the pathophysiology of MDD. In this study, we observed that AGMAT expression increased in the ventral hippocampus rather than in the medial prefrontal cortex in the chronic restraint stress (CRS) animal model of depression. Furthermore, we found that AGMAT overexpression in the ventral hippocampus elicited depressive- and anxiety-like behaviors, whereas knockdown of AGMAT exhibited antidepressant and anxiolytic effects in CRS animals. Field and whole-cell recordings of hippocampal CA1 revealed that AGMAT blockage increased Schaffer collateral-CA1 excitatory synaptic transmission, which was expressed both pre- and post-synaptically and was probably due to the inhibition of AGMAT-expressing local interneurons. Therefore, our results suggest that dysregulation of AGMAT is involved in the pathophysiology of depression and is a potential target for designing more effective antidepressants with fewer adverse effects to offer a better therapy for depression.

Olfactory Dysfunction in Mental Illness.

Olfactory dysfunction contributes to the psychopathology of mental illness. In this review, we describe the neurobiology of olfaction, and the most common olfactory alterations in several mental illnesses. We also highlight the role, hitherto underestimated, that the olfactory pathways play in the regulation of higher brain functions and its involvement in the pathophysiology of psychiatric disorders, as well as the effect of inflammation on neurogenesis as a possible mechanism involved in olfactory dysfunction in psychiatric conditions. The olfactory deficits present in anxiety, depression, schizophrenia or bipolar disorder consist of specific alterations of different components of the sense of smell, mainly the identification of odours, as well as the qualifications of their hedonic valence (pleasant or unpleasant). Epidemiological findings have shown that both environmental factors, such as air pollutants, and inflammatory disease of the upper respiratory tract, can contribute to an increased risk of mental illness, at least in part, due to peripheral inflammatory mechanisms of the olfactory system. In this review, we describe the neurobiology of olfaction, and the most common olfactory function alterations in several psychiatric conditions and its role as a useful symptom for the differential diagnosis. We also highlight the effect of inflammation on neurogenesis as a possible mechanism involved in olfactory dysfunction in these psychiatric conditions.

MicroRNA binding site variation is enriched in psychiatric disorders.

Psychiatric disorders have a polygenic architecture, often associated with dozens or hundreds of independent genomic loci. Most associated loci impact noncoding regions of the genome, suggesting that the majority of disease heritability originates from the disruption of regulatory sequences. While most research has focused on variants that modify regulatory DNA elements, those affecting cis-acting RNA sequences, such as miRNA binding sites, are also likely to have a significant impact. We intersected genome-wide association study (GWAS) summary statistics with the dbMTS database of predictions for miRNA binding site variants (MBSVs). We compared the distributions of MBSV association statistics to non-MBSVs within brain-expressed 3'UTR regions. We aggregated GWAS pvalues at the gene, pathway, and miRNA family levels to investigate cellular functions and miRNA families strongly associated with each trait. We performed these analyses in several psychiatric disorders as well as nonpsychiatric traits for comparison. We observed significant enrichment of MBSVs in schizophrenia, depression, bipolar disorder, and anorexia nervosa, particularly in genes targeted by several miRNA families, including miR-335-5p, miR-21-5p/590-5p, miR-361-5p, and miR-557, and a nominally significant association between miR-323b-3p MBSVs and schizophrenia risk. We identified evidence for the association between MBSVs in synaptic gene sets in schizophrenia and bipolar disorder. We also observed a significant association of MBSVs in other complex traits including type 2 diabetes. These observations support the role of miRNA in the pathophysiology of psychiatric disorders and suggest that MBSVs are an important class of regulatory variants that have functional implications for many disorders, as well as other complex human traits.

T-type Ca2+ channels and inward rectifier K+ channels contribute to the orexin-induced facilitation of GABAergic transmission onto pyramidal neurons in the prefrontal cortex of juvenile mice

Orexin is a neuropeptide restrictedly synthesized in the hypothalamus, but extensively modulates the whole brain region activity including prefrontal cortex (PFC), and involved in the pathophysiology of psychiatric disorders. GABAergic interneurons in the mPFC are a promising pharmacological target for developing antidepressant therapies. Here, we examined the effects of the orexin on GABAergic transmission onto pyramidal neurons in the deep layers of the mPFC. We found that bath application of orexin dose-dependently increased the amplitude of evoked IPSCs (eIPSCs). Orexin increased the frequency but not the amplitude of miniature IPSCs (mIPSCs). Ca2+ influx through T-type voltage-gated Ca2+ channels is required for orexin-induced increases in GABA release. We also found orexin increases GABA release probability and the number of releasable vesicles. Orexin depolarizes somatostatin (Sst) interneurons without effects on the firing rate of action potentials (APs) of Sst interneurons. Orexin-induced depolarization of Sst interneurons is independent of extracellular Na+, Ca2+ and T-type Ca2+ channels, but requires inward rectifier K+ channels (Kirs). The present study suggests that orexin enhances GABAergic transmission onto mPFC pyramidal neurons through inhibiting Kirs on Sst interneurons, which further depolarizes interneurons leading to increase in Ca2+ influx via T-type Ca2+ channels. Our results may provide a cellular and molecular mechanism that helps explain the physiological functions of orexin in the brain.

Astrocyte Activation, but not Microglia, Is Associated with the Experimental Mouse Model of Schizophrenia Induced by Chronic Ketamine.

Ketamine is a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors. Many experimental studies have shown that ketamine can induce cognitive impairments and schizophrenia-like symptoms. While much data have demonstrated that glial cells are associated with the pathophysiology of psychiatric disorders, including schizophrenia, the response of glial cells to ketamine and its significance to schizophrenia are not clear. The present study was intended to explore whether chronic ketamine treatment would induce behavioral and glial changes in mice. First, ketamine was used to stimulate behavioral abnormalities similar to schizophrenia evaluated by the open field test, elevated plus-maze test, Y maze test, novel object recognition test, and tail suspension test. Secondly, histopathology and Nissl staining were performed. Meanwhile, immunofluorescence was used to evaluate the expression levels of IBA-1 (a microglial marker) and GFAP (an astrocyte marker) in the mouse hippocampus for any change. Then, ELISA was used to analyze proinflammatory cytokine levels for any change. Our results showed that ketamine (25mg/kg, i.p., qid, 12days) induced anxiety, recognition deficits, and neuronal injury in the hippocampus. Moreover, chronic ketamine treatment enhanced GFAP expression in CA1 and DG regions of the hippocampus but did not influence the expression of IBA-1. Ketamine also increased the levels of IL-1β, IL-6, and TNF-α in the mouse hippocampus. Our study created a new procedure for ketamine administration, which successfully induce negative symptoms and cognitive-behavioral defects in schizophrenia by chronic ketamine. This study furtherrevealed that an increase in astrocytosis, but not microglia, is associated with the mouse model of schizophrenia caused by ketamine. In summary, hippocampal astrocytes may be involved in the pathophysiology of ketamine-induced schizophrenia-like phenotypes through reactive transformation and regulation of neuroinflammation.

Potential Candidates for Biomarkers in Bipolar Disorder: A Proteomic Approach through Systems Biology.

Bipolar disorder (BD) is one of the most disabling diseases characterized by severe humor fluctuation. It is accompanied by cognitive and functional impairment in addiction to high suicide rates. BD is often underdiagnosed and treated incorrectly because many of the reported symptoms are not exclusive to the disorder. Once the diagnosis is exclusively clinical, it is not possible to state precisely. From that, proteomic approaches were used to identify, in a large scale, all proteins involved in cellular or tissue processes. This review aggregate data from blood proteomes, by using protein association network, of subjects with BD and healthy controls to suggest dysfunctional molecular pathways involved in disease. Original articles containing proteomic analysis were searched in PubMed. Seven studies were selected and data were extracted for posterior analysis. A protein-protein interaction network was created by STRING database. A final set of proteins in this network were employed as input in ClueGO and, the main biological process was visualized using R package pathview. The analysis revealed proteins associated with many biological processes, including growth and endocrine regulation, iron transportation, protease inhibition, protection against pathogens and cholesterol transport. Moreover, pathway analysis indicated the association of uncovered proteins with two main metabolic pathways: complement system and coagulation cascade. Thus, a better understanding on the pathophysiology of psychiatric disorders and the identification of potential biomarker candidates are essential to improve diagnostic, prognostic and design pharmacological strategies.

P108. Neighborhood Disadvantage Associated With Differential Neural Response to Predictable and Unpredictable Threat in a Community Sample of Youth

Childhood socioeconomic disadvantage is a form of adversity associated with alterations in critical frontolimbic circuits that are involved in the pathophysiology of psychiatric disorders. Most work has focused on individual-level socioeconomic position, yet individuals living in deprived communities typically encounter additional environmental stressors that may have unique effects on the brain and, consequently, health outcomes.

Neighborhood Disadvantage Associated With Blunted Amygdala Reactivity to Predictable and Unpredictable Threat in a Community Sample of Youth

BackgroundChildhood socioeconomic disadvantage is a form of adversity associated with alterations in critical frontolimbic circuits involved in the pathophysiology of psychiatric disorders. Most work has focused on individual-level socioeconomic position, yet individuals living in deprived communities typically encounter additional environmental stressors that have unique effects on the brain and health outcomes. Notably, chronic and unpredictable stressors experienced in the everyday lives of youth living in disadvantaged neighborhoods may impact neural responsivity to uncertain threat. MethodsA community sample of children (N = 254) ages 8 to 15 years (mean = 12.15) completed a picture anticipation task during a functional magnetic resonance imaging scan, during which neutral and negatively valenced photos were presented in a temporally predictable or unpredictable manner. Area Deprivation Index (ADI) scores were derived from participants’ home addresses as an index of relative neighborhood disadvantage. Voxelwise analyses examined interactions of ADI, valence, and predictability on neural response to picture presentation. ResultsThere was a significant ADI × valence interaction in the middle temporal gyrus, anterior cingulate cortex, hippocampus, and amygdala. Higher ADI was associated with less amygdala activation to negatively valenced images. ADI also interacted with predictability. Higher ADI was associated with greater activation of lingual and calcarine gyri for unpredictably presented stimuli. There was no three-way interaction of ADI, valence, and predictability. ConclusionsNeighborhood disadvantage may impact how the brain perceives and responds to potential threats. Future longitudinal work is critical for delineating how such effects may persist across the life span and how health outcomes may be modifiable with community-based interventions and policies.

Trends in big data analyses by multicenter collaborative translational research in psychiatry.

The underlying pathologies of psychiatric disorders, which cause substantial personal and social losses, remain unknown, and their elucidation is an urgent issue. To clarify the core pathological mechanisms underlying psychiatric disorders, in addition to laboratory‐based research that incorporates the latest findings, it is necessary to conduct large‐sample‐size research and verify reproducibility. For this purpose, it is critical to conduct multicenter collaborative research across various fields, such as psychiatry, neuroscience, molecular biology, genomics, neuroimaging, cognitive science, neurophysiology, psychology, and pharmacology. Moreover, collaborative research plays an important role in the development of young researchers. In this respect, the Enhancing Neuroimaging Genetics through Meta‐Analysis (ENIGMA) consortium and Cognitive Genetics Collaborative Research Organization (COCORO) have played important roles. In this review, we first overview the importance of multicenter collaborative research and our target psychiatric disorders. Then, we introduce research findings on the pathophysiology of psychiatric disorders from neurocognitive, neurophysiological, neuroimaging, genetic, and basic neuroscience perspectives, focusing mainly on the findings obtained by COCORO. It is our hope that multicenter collaborative research will contribute to the elucidation of the pathological basis of psychiatric disorders.

Mind-Brain Dynamics in the Pathophysiology of Psychiatric Disorders

Mind-Brain Dynamics in the Pathophysiology of Psychiatric Disorders

Dynamic Causal Modeling of the Prefrontal/Amygdala Network During Processing of Emotional Faces.

Introduction: The importance of the amygdala/medial orbitofrontal cortex (OFC) network during processing of emotional stimuli, emotional faces in particular, is well established. This premise is supported by converging evidence from animal models, human neuroanatomical results, and neuroimaging studies. However, there is missing evidence from human brain connectivity studies that the OFC and no other prefrontal brain areas such as the dorsolateral prefrontal cortex (DLPFC) or ventrolateral prefrontal cortex (VLPFC) are responsible for amygdala regulation in the functional context of emotional face stimuli. Methods: Dynamic causal modeling of ultrahigh-field functional magnetic resonance imaging data acquired at 7 Tesla in 38 healthy subjects and a well-established paradigm for emotional face processing were used to assess the central role of the OFC to provide empirical validation for the assumed network architecture. Results: Using Bayesian model selection, it is demonstrated that indeed the OFC, and not the VLPFC and the DLPFC, downregulates amygdala activation during the emotion discrimination task. In addition, Bayesian model averaging group results were rigorously tested using bootstrapping, further corroborating these findings and providing an estimator for robustness and optimal sample sizes. Discussion: While it is true that VLPFC and DLPFC are relevant for the processing of emotional faces and are connected to the OFC, the OFC appears to be a central hub for the prefrontal/amygdala interaction. Impact statement Using dynamic causal modeling (DCM), abnormal effective connectivity in the orbitofrontal cortex (OFC)/amygdala network has been repeatedly observed in the pathophysiology of psychiatric disorders. However, it has to be considered that these findings are all based on the a priori assumption of the OFC being the central area for prefrontal control regulating amygdala activation. This is particularly important, as DCM results conditionally depend on the underlying model space used for model selection. Using Bayesian model comparison methods, it is shown that the OFC (and not the dorsolateral prefrontal cortex or ventrolateral prefrontal cortex) engages in amygdala downregulation in the context emotional face processing.

Dopamine signaling impairs ROS modulation by mitochondrial hexokinase in human neural progenitor cells.

Dopamine signaling has numerous roles during brain development. In addition, alterations in dopamine signaling may be also involved in the pathophysiology of psychiatric disorders. Neurodevelopment is modulated in multiple steps by reactive oxygen species (ROS), byproducts of oxidative metabolism that are signaling factors involved in proliferation, differentiation, and migration. Hexokinase (HK), when associated with the mitochondria (mt-HK), is a potent modulator of the generation of mitochondrial ROS in the brain. In the present study, we investigated whether dopamine could affect both the activity and redox function of mt-HK in human neural progenitor cells (NPCs). We found that dopamine signaling via D1R decreases mt-HK activity and impairs ROS modulation, which is followed by an expressive release of H2O2 and impairment in calcium handling by the mitochondria. Nevertheless, mitochondrial respiration is not affected, suggesting specificity for dopamine on mt-HK function. In neural stem cells (NSCs) derived from induced-pluripotent stem cells (iPSCs) of schizophrenia patients, mt-HK is unable to decrease mitochondrial ROS, in contrast with NSCs derived from healthy individuals. Our data point to mitochondrial hexokinase as a novel target of dopaminergic signaling, as well as a redox modulator in human neural progenitor cells, which may be relevant to the pathophysiology of neurodevelopmental disorders such as schizophrenia.

Transcriptome Profiling of Dysregulated GPCRs Reveals Overlapping Patterns across Psychiatric Disorders and Age-Disease Interactions.

G-protein-coupled receptors (GPCRs) play an integral role in the neurobiology of psychiatric disorders. Almost all neurotransmitters involved in psychiatric disorders act through GPCRs, and GPCRs are the most common targets of therapeutic drugs currently used in the treatment of psychiatric disorders. However, the roles of GPCRs in the etiology and pathophysiology of psychiatric disorders are not fully understood. Using publically available datasets, we performed a comprehensive analysis of the transcriptomic signatures of G-protein-linked signaling across the major psychiatric disorders: autism spectrum disorder (ASD), schizophrenia (SCZ), bipolar disorder (BP), and major depressive disorder (MDD). We also used the BrainSpan transcriptomic dataset of the developing human brain to examine whether GPCRs that exhibit chronological age-associated expressions have a higher tendency to be dysregulated in psychiatric disorders than age-independent GPCRs. We found that most GPCR genes were differentially expressed in the four disorders and that the GPCR superfamily as a gene cluster was overrepresented in the four disorders. We also identified a greater amplitude of gene expression changes in GPCRs than other gene families in the four psychiatric disorders. Further, dysregulated GPCRs overlapped across the four psychiatric disorders, with SCZ exhibiting the highest overlap with the three other disorders. Finally, the results revealed a greater tendency of age-associated GPCRs to be dysregulated in ASD than random GPCRs. Our results substantiate the central role of GPCR signaling pathways in the etiology and pathophysiology of psychiatric disorders. Furthermore, our study suggests that common GPCRs’ signaling may mediate distinct phenotypic presentations across psychiatric disorders. Consequently, targeting these GPCRs could serve as a common therapeutic strategy to treat specific clinical symptoms across psychiatric disorders.

Plasma fatty acid-binding protein 7 concentration correlates with depression/anxiety, cognition, and positive symptom in patients with schizophrenia

Because of the involvement of the brain in the pathophysiology of psychiatric disorders, obtaining information on the biochemical features that directly contribute to symptoms is challenging. The present study aimed to assess fatty acid-binding protein 7 (FABP7) expressed specifically in the brain and detectable in the peripheral blood and to investigate the correlation between blood FABP7 concentration and symptoms. We recruited 30, 29, and 35 patients with schizophrenia, bipolar disorder, and depression and evaluated using the Positive and Negative Syndrome Scale (PANSS), Young Mania Rating Scale (YMRS), and Hamilton Depression Rating Scale (HAMD-21), respectively. Plasma FABP7 concentrations correlated with PANSS scores (R2 = 0.3305, p < 0.001) but not with other scales. In the analysis of the relationship between five dimensions of schizophrenia symptoms derived from the PANSS 5-factor model and measured plasma FABP7 concentrations, severities of depression/anxiety, cognition, and positive symptom were significantly correlated with plasma FABP7 concentrations. Further molecular investigation of the functional and kinetic analyses of FABP7 is necessary to understand the relationship of this protein with schizophrenia pathology. Nevertheless, the present study suggests that FABP7 can be a biological indicator reflecting the pathogenesis of schizophrenia and has potential applications as a biomarker for diagnosis and symptom assessment.