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

Farsi, Z.; Nicolella, A.; Simmons, S. K.; Aryal, S.; Shepard, N.; Brenner, K.; Lin, S.; Herzog, L. E.; Shin, W.; Gazestani, V.; Song, B.; Bonanno, K.; Keshishian, H.; Carr, S. A.; Macosko, E.; Datta, S. R.; Dejanovic, B.; Kim, E.; Levin, J. Z.; Sheng, M.

doi:10.1101/2022.11.15.516665

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bioRxiv · 10.1101/2022.11.15.516665

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

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Abstract

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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Farsi, Z., Nicolella, A., Simmons, S. K., Aryal, S., Shepard, N., Brenner, K., Lin, S., Herzog, L. E., Shin, W., Gazestani, V., Song, B., Bonanno, K., Keshishian, H., Carr, S. A., Macosko, E., Datta, S. R., Dejanovic, B., Kim, E., Levin, J. Z., Sheng, M.. 2022-11-15. Brain region-specific changes in neurons and glia and dysregulation of dopamine signaling in Grin2a mutant mice. https://doi.org/10.1101/2022.11.15.516665

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