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Altered function and maturation of primary cortical neurons from a 22q11.2 deletion mouse model of schizophrenia.

ABSTRACT: Given its high penetrance, clearly delineated and evolutionary conserved genomic structure, mouse models of the 22q11.2 deletion provide an ideal organism-based and cell-based model of this well-established disease mutation for schizophrenia. In this study we examined the development of changes in intrinsic properties, action potential firing and synaptic transmission using whole-cell patch-clamp recordings of cultured embryonic cortical neurons from Df(16)A +/- and WT mice at DIV7 and DIV14, respectively. Compared to neurons from the WT littermates, significantly increased input resistance and decreased rising rate of action potential was observed in Df(16)A +/- mice at DIV7 but not at DIV14 indicative of delayed neuronal maturation. Neurons from Df(16)A +/- mice also showed significantly higher cellular excitability at both DIV7 and DIV14. Evaluation of Ca2+ homeostasis perturbation caused by 22q11.2 deletion using calcium imaging revealed a significantly lower amplitude of calcium elevation and a smaller area under the curve after depolarization in neurons from Df(16)A +/- mice at both DIV7 and DIV14. Furthermore, the properties of inhibitory synaptic events were significantly altered in Df(16)A +/- mice. We identified changes in mRNA expression profiles, especially in ion channels, receptors, and transporters that may underlie the neurophysiological effects of this mutation. Overall, we show a number of alterations in electrophysiological and calcium homeostatic properties of embryonic cortical neurons from a 22q11.2 deletion mouse model at different culture times and provide valuable insights towards revealing disease mechanisms and discovery of new therapeutic compounds.

SUBMITTER: Sun Z

PROVIDER: S-EPMC5904157 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Altered function and maturation of primary cortical neurons from a 22q11.2 deletion mouse model of schizophrenia.

Sun Ziyi Z Williams Damian J DJ Xu Bin B Gogos Joseph A JA

Translational psychiatry 20180418 1

Given its high penetrance, clearly delineated and evolutionary conserved genomic structure, mouse models of the 22q11.2 deletion provide an ideal organism-based and cell-based model of this well-established disease mutation for schizophrenia. In this study we examined the development of changes in intrinsic properties, action potential firing and synaptic transmission using whole-cell patch-clamp recordings of cultured embryonic cortical neurons from Df(16)A <sup>+/-</sup> and WT mice at DIV7 an ...[more]

PMID: 29666363

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Project description:Individuals with 22q11.2 Deletion Syndrome (22q11.2 DS) are a specific high-risk group for developing schizophrenia (SZ), schizoaffective disorder (SAD) and autism spectrum disorders (ASD). Several genes in the deleted region have been implicated in the development of SZ, e.g., PRODH and DGCR8. However, the mechanistic connection between these genes and the neuropsychiatric phenotype remains unclear. To elucidate the molecular consequences of 22q11.2 deletion in early neural development, we carried out RNA-seq analysis to investigate gene expression in early differentiating human neurons derived from induced pluripotent stem cells (iPSCs) of 22q11.2 DS SZ and SAD patients.Eight cases (ten iPSC-neuron samples in total including duplicate clones) and seven controls (nine in total including duplicate clones) were subjected to RNA sequencing. Using a systems level analysis, differentially expressed genes/gene-modules and pathway of interests were identified. Lastly, we related our findings from in vitro neuronal cultures to brain development by mapping differentially expressed genes to BrainSpan transcriptomes.We observed ~2-fold reduction in expression of almost all genes in the 22q11.2 region in SZ (37 genes reached p-value?<?0.05, 36 of which reached a false discovery rate?<?0.05). Outside of the deleted region, 745 genes showed significant differences in expression between SZ and control neurons (p?<?0.05). Function enrichment and network analysis of the differentially expressed genes uncovered converging evidence on abnormal expression in key functional pathways, such as apoptosis, cell cycle and survival, and MAPK signaling in the SZ and SAD samples. By leveraging transcriptome profiles of normal human brain tissues across human development into adulthood, we showed that the differentially expressed genes converge on a sub-network mediated by CDC45 and the cell cycle, which would be disrupted by the 22q11.2 deletion during embryonic brain development, and another sub-network modulated by PRODH, which could contribute to disruption of brain function during adolescence.This study has provided evidence for disruption of potential molecular events in SZ patient with 22q11.2 deletion and related our findings from in vitro neuronal cultures to functional perturbations that can occur during brain development in SZ.

Dataset Information

Altered function and maturation of primary cortical neurons from a 22q11.2 deletion mouse model of schizophrenia.

Publications

Altered function and maturation of primary cortical neurons from a 22q11.2 deletion mouse model of schizophrenia.

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