CYFIP1 dosages exhibit divergent behavioral impact via diametric regulation of NMDAR complex translation in mouse models of psychiatric disorders
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PROVIDER: PRJNA702462 | ENA |
REPOSITORIES: ENA
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Project description:Gene dosage imbalance caused by copy number variations (CNVs) are prominent contributors to brain disorders. 15q11.2 CNV duplications and deletions have been associated with autism spectrum disorder (ASD) and schizophrenia (SCZ), respectively. The mechanism underlying these diametric contributions remain unclear. Here we established both loss-of-function and gain-of-function mouse models of Cyfip1, one of four genes within 15q11.2 CNVs and these mice exhibited both distinct and shared behavioral abnormalities related to ASD and SCZ. RIP-seq analysis identified mRNA targets of CYFIP1 in vivo, including postsynaptic NMDAR complex components. These mouse models showed diametric changes in levels of postsynaptic NMDAR complex components at synapses due to dysregulated protein translation, resulting in bidirectional alteration of NMDAR-mediated signaling. Importantly, pharmacological balancing of NMDAR signaling in mouse models with diametric CYFIP1 dosages rescues behavioral abnormalities. Our integrated analyses provide insight into how gene dosage imbalance caused by CNVs may contribute to divergent neuropsychiatric disorders.
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Project description:MicroRNAs have been implicated in the pathology not only of cancer, but also of psychiatric diseases, such as bipolar disorder and schizophrenia. As several psychiatric disorders share the same risk genes, we hypothesized that this microRNA could also be associated with attention-deficit/hyperactivity disorder (ADHD) and that this association to psychiatric disorders might be due to the variable number of tandem repeats (VNTR) polymorphism within the internal miR-137 (Imir137) promoter (PMID 18316599; PMID 25154622). To further understand the role of the microRNA 137 in the brain a knock-down of miR-137 expression in SH-SY5Y neuroblastoma cells was performed followed by expression analysis using a microarray.
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Project description:Mice modeling human CNVs associated with psychiatric disorders
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Project description:Abnormal N-methyl-D-aspartate receptor (NMDAR) function has been implicated in the pathophysiology of schizophrenia. D-serine is an important NMDAR modulator, and to elucidate the role of the D-serine synthesis enzyme serine racemase (Srr) in schizophrenia, we identified and characterized mice with an ENU-induced mutation that results in a complete loss of Srr activity and drastically reduced D-serine levels. Mutant mice displayed behaviors relevant to schizophrenia, including impairments in prepulse inhibition, sociability and spatial discrimination. Behavioral deficits were rescued by D-serine and the atypical antipsychotic clozapine, and were conversely, amplified by NMDAR inhibition. Expression profiling revealed that the Srr mutation influenced several genes that have been linked to schizophrenia and cognitive ability. Furthermore, analysis of Srr genetic variants in humans identified a robust association with schizophrenia. This study demonstrates that aberrant serine racemase function and diminished D-serine may contribute to schizophrenia pathogenesis, and that D-serine may be a beneficial form of treatment Keywords: genetic-mutant vs. wildtype comparison
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