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[...]the structural-functional connectivity (SC-FC) relationship is strengthened with age, which is consistent with the finding that significant correlations along intra-hemispheric tracts are observed between structural connectivity and functional connectivity in adults but not in children. [...]the maturation of some functional connections in the default-mode network precedes that of structural connectivity. Han Chinese participants aged 16 to 55 years who met the criteria of MDD as specified in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) were recruited from the Mental Health Center of West China Hospital of Sichuan University. The Benjamini–Hochberg procedure was used to control false discovery rates (FDRs) of multiple tests in comparing SC-FC coupling and correlation coefficients between patients with MDD and HCs. There was a statistically significant difference in correlation coefficients between SC-FC coupling of SMA_R and DMS_MCL_S in patients with MDD and HCs (P <0.01, q = 0.02) after correction for multiple testing [Table 1].

The mechanisms by which prenatal immune activation increase the risk for neuropsychiatric disorders are unclear. Here, we generated developmental cortical interneurons (cINs)—which are known to be affected in schizophrenia (SCZ) when matured—from induced pluripotent stem cells (iPSCs) derived from healthy controls (HCs) and individuals with SCZ and co-cultured them with or without activated microglia. Co-culture with activated microglia disturbed metabolic pathways, as indicated by unbiased transcriptome analyses, and impaired mitochondrial function, arborization, synapse formation and synaptic GABA release. Deficits in mitochondrial function and arborization were reversed by alpha lipoic acid and acetyl-l-carnitine treatments, which boost mitochondrial function. Notably, activated-microglia-conditioned medium altered metabolism in cINs and iPSCs from HCs but not in iPSCs from individuals with SCZ or in glutamatergic neurons. After removal of activated-microglia-conditioned medium, SCZ cINs but not HC cINs showed prolonged metabolic deficits, which suggests that there is an interaction between SCZ genetic backgrounds and environmental risk factors.When co-cultured with activated microglia, iPSC-derived interneurons from individuals with schizophrenia and from healthy controls show defects in metabolic pathways, but only the interneurons from individuals with schizophrenia showed prolonged metabolic deficits.

Schizophrenia (SCZ) is a neurodevelopmental disorder. Thus, studying pathogenetic mechanisms underlying SCZ requires studying the development of brain cells. Cortical interneurons (cINs) are consistently observed to be abnormal in SCZ postmortem brains. These abnormalities may explain altered gamma oscillation and cognitive function in patients with SCZ. Of note, currently used antipsychotic drugs ameliorate psychosis, but they are not very effective in reversing cognitive deficits. Characterizing mechanisms of SCZ pathogenesis, especially related to cognitive deficits, may lead to improved treatments. We generated homogeneous populations of developing cINs from 15 healthy control (HC) iPSC lines and 15 SCZ iPSC lines. SCZ cINs, but not SCZ glutamatergic neurons, show dysregulated Oxidative Phosphorylation (OxPhos) related gene expression, accompanied by compromised mitochondrial function. The OxPhos deficit in cINs could be reversed by Alpha Lipoic Acid/Acetyl-L-Carnitine (ALA/ALC) but not by other chemicals previously identified as increasing mitochondrial function. The restoration of mitochondrial function by ALA/ALC was accompanied by a reversal of arborization deficits in SCZ cINs. OxPhos abnormality, even in the absence of any circuit environment with other neuronal subtypes, appears to be an intrinsic deficit in SCZ cINs.

Background Recent genome-wide association studies have linked voltage-gated calcium channel genes to bipolar disorder (BD), in which CACNB2 gene rs11013860 is respectively reported. Less is known, though, about how precisely its polymorphism affects both the structure and function of the brain. Methods 173 BD patients and 207 healthy controls (HCs) were underwent structural and functional magnetic resonance imaging scan and genotyped for CACNB2 rs11013860. Grey matter volume (GMV), regional homogeneity (ReHo) and degree centrality (DC) were used to examine the brain structure, functional activity and connectivity of these participants. Results The emotional circuits in BD patients, such as cerebellum, insula, cingulate gyrus, fusiform gyrus, superior frontal gyrus, superior / middle temporal gyrus, middle occipital gyrus, lingual gyrus, precuneus, putamen, hippocampus and parahippocampal gyrus, were the main areas where GMV, ReHo, and DC differed from HCs. And the right anterior and posterior cerebellar lobes, parahippocampal gyrus as well as lingual gyrus showed an interaction between CACNB2 rs11013860 genotypes and diagnoses in GMV. In addition, there was a significant step-wise increase of GMV with decreased dosage of the A risk allele in HCs, but this pattern of relationship was absent in BD patients. No interaction between BD and CACNB2 rs11013860 was found in ReHo and DC. Conclusions These results suggest that the polymorphism of CACNB2 rs11013860 in BD patients may be associated with brain structural abnormalities in cerebellar, limbic system and other brain regions, perhaps contributing to the disease.

We generated cortical interneurons (cINs) from induced pluripotent stem cells derived from 14 healthy controls and 14 subjects with schizophrenia. Both healthy control cINs and schizophrenia cINs were authentic, fired spontaneously, received functional excitatory inputs from host neurons, and induced GABA-mediated inhibition in host neurons in vivo. However, schizophrenia cINs had dysregulated expression of protocadherin genes, which lie within documented schizophrenia loci. Mice lacking protocadherin-α showed defective arborization and synaptic density of prefrontal cortex cINs and behavioral abnormalities. Schizophrenia cINs similarly showed defects in synaptic density and arborization that were reversed by inhibitors of protein kinase C, a downstream kinase in the protocadherin pathway. These findings reveal an intrinsic abnormality in schizophrenia cINs in the absence of any circuit-driven pathology. They also demonstrate the utility of homogenous and functional populations of a relevant neuronal subtype for probing pathogenesis mechanisms during development.Shao et al. report that interneurons derived from iPSCs from schizophrenia patients have altered protocadherin expression and synaptic and arborization deficits. A PKC inhibitor, acting downstream of protocadherin, reversed the arborization deficit.

Schizophrenia is a heritable, heterogeneous common psychiatric disorder. In this study, we evaluated the hypothesis that de novo variants (DNVs) contribute to the pathogenesis of schizophrenia. We performed exome sequencing in Chinese patients (N = 45) with schizophrenia and their unaffected parents (N = 90). Forty genes were found to contain DNVs. These genes had enriched transcriptional co-expression profile in prenatal frontal cortex (Bonferroni corrected p  < 9.1 × 10 −3 ) and in prenatal temporal and parietal regions (Bonferroni corrected p  < 0.03). Also, four prenatal anatomical subregions (VCF, MFC, OFC and ITC) have shown significant enrichment of connectedness in co-expression networks. Moreover, four genes ( LRP1 , MACF1 , DICER1 and ABCA2 ) harboring the damaging de novo mutations are strongly prioritized as susceptibility genes by multiple evidences. Our findings in Chinese schizophrenic patients indicate the pathogenic role of DNVs, supporting the hypothesis that schizophrenia is a neurodevelopmental disease.

The current study aimed to explore age-variant trait differences of cortical gray matter volume (GMV) in a unique sample of first-episode and treatment-naïve patients with schizophrenia. A total of 158 subjects, including 26 adolescent-onset patients and 49 adult-onset patients as well as 83 age- and gender-matched controls were scanned using a 3T MRI scanner. Voxel-based morphometry (VBM) following Diffeomorphic Anatomical Registration Through Exponentiated Lie algebra (DARTEL) was used to explore group differences between patients and controls in regional GMV. We found that patients with schizophrenia had decreased GMV in the left parietal postcentral region that extended to the left frontal regions, the right middle temporal gyrus, the occipital lobe and the right cerebellum posterior pyramis. Further analysis showed a distinct pattern of gray matter alterations in adolescent-onset patients compared with both healthy controls and adult-onset patients. Relative to healthy controls, adolescent-onset patients showed GMV alterations in the left parietal postcentral gyrus, parahippocampal gyrus and right cerebellum posterior pyramis, while GMV deficits in adult-onset patients were focused on the cingulo-fronto-temporal module and right occipital regions. Our study identified differential cortical gray matter deficits between adolescent- and adulthood-onset patients with schizophrenia, which suggests that the cortical abnormalities in schizophrenia are likely adjusted by the developmental community structure of the human brain.

Promising biomarkers would be used to improve the determination of diagnosis and severity, as well as the prediction of symptomatic and functional outcomes of schizophrenia. In this study, we used three different mouse models induced by a genetic factor (PV-Cre; ErbB4−/−, G group), an environmental stressor (adolescent social isolation, G group), and a combination of genetic factor and environmental stressor (PV-Cre; ErbB4−/− mice with isolation, G × E group). Attenuated PPI (%) confirmed the successful establishment of three schizophrenia-like mouse models. To evaluate whether neuropeptide levels in plasma would be potential biomarkers of different schizophrenia models in our work, we used MILLIPLEX® MAP method to simultaneously measure 6 critical neuropeptides in plasma. Among the evaluated neuropeptides, increased neurotensin tends to be associated with genetic factors of schizophrenia, increased orexin A seems to be a biomarker of an interplay between genetic and social isolation, while higher plasma oxytocin might be more apt to be responsive to social isolation. The potential biomarkers are mostly independent of sex. This research would provide novel clues to develop circulating biomarkers of plasma neuropeptides for multifactorial schizophrenia. •Both genetic and environmental factors were considered for the schizophrenia models.•Six neuropeptides were simultaneously measured using only 250 μL sample.•Different neuropeptides might be responsive to specific pathological factors.•Novel clues to develop circulating biomarkers for multifactorial schizophrenia

BackgroundElevated platelet count (PLTc) is associated with first-episode schizophrenia and adverse outcomes in individuals with precursory psychosis. However, the impact of antipsychotic medications on PLTc and its association with symptom improvement remain unclear.AimsWe aimed to investigate changes in PLTc levels following antipsychotic treatment and assess whether PLTc can predict antipsychotic responses and metabolic changes after accounting for other related variables.MethodsA total of 2985 patients with schizophrenia were randomised into seven groups. Each group received one of seven antipsychotic treatments and was assessed at 2, 4 and 6 weeks. Clinical symptoms were evaluated using the positive and negative syndrome scale (PANSS). Additionally, we measured blood cell counts and metabolic parameters, such as blood lipids. Repeated measures analysis of variance was used to examine the effect of antipsychotics on PLTc changes, while structural equation modelling was used to assess the predictive value of PLTc on PANSS changes.ResultsPLTc significantly increased in patients treated with aripiprazole (F=6.00, p=0.003), ziprasidone (F=7.10, p<0.001) and haloperidol (F=3.59, p=0.029). It exhibited a positive association with white blood cell count and metabolic indicators. Higher baseline PLTc was observed in non-responders, particularly in those defined by the PANSS-negative subscale. In the structural equation model, PLTc, white blood cell count and a latent metabolic variable predicted the rate of change in the PANSS-negative subscale scores. Moreover, higher baseline PLTc was observed in individuals with less metabolic change, although this association was no longer significant after accounting for baseline metabolic values.ConclusionsPlatelet parameters, specifically PLTc, are influenced by antipsychotic treatment and could potentially elevate the risk of venous thromboembolism in patients with schizophrenia. Elevated PLTc levels and associated factors may impede symptom improvement by promoting inflammation. Given PLTc’s easy measurement and clinical relevance, it warrants increased attention from psychiatrists.Trial registration numberChiCTR-TRC-10000934.