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

Zohreh Farsi¹, Ally Nicolella², Sean K Simmons³, Sameer Aryal², Nate Shepard², Kira Brenner², Sherry Lin⁴, Linnea Herzog², Sean P Moran², Katherine J Stalnaker², Wangyong Shin⁵, Vahid Gazestani², Bryan J Song², Kevin Bonanno⁶, Hasmik Keshishian⁶, Steven A Carr⁶, Jen Q Pan², Evan Z Macosko⁷, Sandeep Robert Datta⁴, Borislav Dejanovic², Eunjoon Kim⁸, Joshua Z Levin³, Morgan Sheng⁹

Affiliations

¹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: zfarsi@broadinstitute.org.
² Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
⁵ Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, South Korea.
⁶ Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁷ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Massachusetts General Hospital, Department of Psychiatry, Boston, MA, USA.
⁸ Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, South Korea; Department of Biological Sciences, Korea Advanced Institute for Science and Technology, Daejeon, South Korea.
⁹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: msheng@broadinstitute.org.

PMID: 37657442
DOI: 10.1016/j.neuron.2023.08.004

Free article

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

Zohreh Farsi et al. Neuron. 2023.

Free article

. 2023 Nov 1;111(21):3378-3396.e9.

doi: 10.1016/j.neuron.2023.08.004. Epub 2023 Aug 31.

Authors

Affiliations

¹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: zfarsi@broadinstitute.org.
² Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
⁵ Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, South Korea.
⁶ Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁷ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Massachusetts General Hospital, Department of Psychiatry, Boston, MA, USA.
⁸ Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, South Korea; Department of Biological Sciences, Korea Advanced Institute for Science and Technology, Daejeon, South Korea.
⁹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: msheng@broadinstitute.org.

PMID: 37657442
DOI: 10.1016/j.neuron.2023.08.004

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.

Keywords: GRIN2A; GRIN2B; SCHEMA; dopamine signaling; glutamate signaling; hyper-dopamine; hypo-glutamate; multi-omics; schizophrenia; synaptic signaling.

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Conflict of interest statement

Declaration of interests M.S. is cofounder and SAB member of Neumora Therapeutics and serves on the SAB of Biogen, ArcLight, Vanqua Bio, and Proximity Therapeutics. M.S. is on the advisory board of Neuron. S.A.C. is a member of the scientific advisory boards of Kymera, PTM BioLabs, Seer, and PrognomIQ.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

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Full Text Sources

Molecular Biology Databases

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