Brain region-specific changes in neurons and glia and dysregulation of dopamine signaling in Grin2a mutant mice
bioRxiv (Cold Spring Harbor Laboratory)(2022)
摘要
Schizophrenia disease mechanisms remain poorly understood, in large part due to a lack of valid animal models. Rare heterozygous loss-of-function mutations in GRIN2A , encoding a subunit of the NMDA (N-methyl-d-aspartate) receptor, greatly increase the risk of schizophrenia. By transcriptomic, proteomic, electroencephalogram (EEG) recording and behavioral analysis, we report that heterozygous Grin2a mutant mice show: (i) large-scale gene expression changes across multiple brain regions and in neuronal (excitatory and inhibitory) and non-neuronal cells (astrocytes, oligodendrocytes); (ii) evidence of reduced activity in prefrontal cortex and increased activity in hippocampus and striatum; (iii) elevated dopamine signaling in striatum; (iv) altered cholesterol biosynthesis in astrocytes; (v) reduction of glutamatergic receptor signalin g proteins in the synapse; (iv) heightened gamma oscillation power in EEG; (vi) aberrant locomotor behavioral pattern opposite of that induced by antipsychotic drugs. These findings reveal potential pathophysiologic mechanisms, provide support for both the “hypo-glutamate” and “hyper-dopamine” hypotheses of schizophrenia, and underscore the utility of Grin2a -deficient mice as a new genetic model of schizophrenia.
### Competing Interest Statement
Morgan Sheng is scientific cofounder and SAB member of Neumora Therapeutics, and SAB member of Biogen, VanquaBio, Cerevel, and ArcLight Therapeutics.
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关键词
dopamine,in<i>grin2a</i>mutant mice,neurons,glia,region-specific
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