Brain region-specific changes in neurons and glia and dysregulation of dopamine signaling in Grin2a mutant mice
Creators
- Farsi, Zohreh1
- Nicolella, Ally2
- Simmons, Sean2
- Aryal, Sameer2
- Shepard, Nate2
- Brenner, Kira2
- Lin, Sherry3
- Herzog, Linnea1
- Shin, Wangyong4
- Gazestani, Vahid1
- Song, Bryan1
- Bonanno, Kevin5
- Keshishian, Hasmik5
- Carr, Steven5
- Macosko, Evan1
- Datta, Sandeep3
- Dejanovic, Borislav1
- Kim, Eunjoon6
- Levin, Joshua1
- Sheng, Morgan1
- 1. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- 2. 1 9 Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- 3. Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- 4. Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, South Korea
- 5. The Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- 6. Department of Biological Sciences, Korea Advanced Institute for Science and Technology, Daejeon, South Korea
Description
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.
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