論文 - 詳細
| RRC ID | 87257 |
|---|---|
| 著者 | Farsi Z, Nicolella A, Simmons SK, Aryal S, Shepard N, Brenner K, Lin S, Herzog L, Moran SP, Stalnaker KJ, Shin W, Gazestani V, Song BJ, Bonanno K, Keshishian H, Carr SA, Pan JQ, Macosko EZ, Datta SR, Dejanovic B, Kim E, Levin JZ, Sheng M. |
| タイトル | Brain-region-specific changes in neurons and glia and dysregulation of dopamine signaling in Grin2a mutant mice. |
| ジャーナル | Neuron |
| 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. |
| 巻・号 | 111(21) |
| ページ | 3378-3396.e9 |
| 公開日 | 2023-11-1 |
| DOI | 10.1016/j.neuron.2023.08.004 |
| PII | S0896-6273(23)00585-8 |
| PMID | 37657442 |
| MeSH | Animals Brain / metabolism Disease Models, Animal Dopamine* / metabolism Mice Neuroglia / metabolism Neurons / metabolism Prefrontal Cortex / metabolism Proteomics* Receptors, N-Methyl-D-Aspartate* / genetics |
| IF | 14.415 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 36 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.2 |
| リソース情報 | |
| 実験動物マウス | RBRC02256 |