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Brain-region-specific changes in neurons and glia and dysregulation of dopamine signaling in Grin2a mutant miceHot Paper

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Title
Brain-region-specific changes in neurons and glia and dysregulation of dopamine signaling in Grin2a mutant mice
Author(s)
Farsi, Zohreh; Nicolella, Ally; Simmons, Sean K.; Aryal, Sameer; Shepard, Nate; Brenner, Kira; Lin, Sherry; Herzog, Linnea; Moran, Sean P.; Stalnaker, Katherine J.; Wangyong Shin; Gazestani, Vahid; Song, Bryan J.; Bonanno, Kevin; Keshishian, Hasmik; Carr, Steven A.; Pan, Jen Q.; Macosko, Evan Z.; Datta, Sandeep Robert; Dejanovic, Borislav; Eunjoon Kim; Levin, Joshua Z.; Sheng, Morgan
Publication Date
2023-11
Journal
Neuron, v.111, no.21, pp.3378 - 3396.e9
Publisher
Cell Press
Abstract
A genetically valid animal model could transform our understanding of schizophrenia (SCZ) disease mechanisms. Rare heterozygous loss-of-function (LoF) mutations in GRIN2A, encoding a subunit of the NMDA receptor, greatly increase the risk of SCZ. By transcriptomic, proteomic, and behavioral analyses, we report that heterozygous Grin2a mutant mice show (1) large-scale gene expression changes across multiple brain regions and in neuronal (excitatory and inhibitory) and non-neuronal cells (astrocytes and oligodendrocytes), (2) evidence of hypoactivity in the prefrontal cortex (PFC) and hyperactivity in the hippocampus and striatum, (3) an elevated dopamine signaling in the striatum and hypersensitivity to amphetamine-induced hyperlocomotion (AIH), (4) altered cholesterol biosynthesis in astrocytes, (5) a reduction in glutamatergic receptor signaling proteins in the synapse, and (6) an aberrant locomotor 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 SCZ, and underscore the utility of Grin2a-deficient mice as a genetic model of SCZ. © 2023 The Author(s)
URI
https://pr.ibs.re.kr/handle/8788114/14522
DOI
10.1016/j.neuron.2023.08.004
ISSN
0896-6273
Appears in Collections:
Center for Synaptic Brain Dysfunctions(시냅스 뇌질환 연구단) > 1. Journal Papers (저널논문)
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