Brain region-specific changes in neurons and glia and dysregulation of dopamine signaling inGrin2amutant mice

Abstract

SUMMARYSchizophrenia disease mechanisms remain poorly understood, in large part due to a lack of valid animal models. Rare heterozygous loss-of-function mutations inGRIN2A, 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 heterozygousGrin2amutant 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 ofGrin2a-deficient mice as a new genetic model of schizophrenia.

Enhancement of mediodorsal thalamus rescues aberrant belief dynamics in a mouse model with schizophrenia-associated mutation

“…Interestingly, the expression of Grin2a is not limited to MD, and it remains to be discovered how mutations of Grin2a severely affected MD activity. Transcriptomic and proteomic studies showed molecular evidence for hypofunction in the prefrontal cortex in the heterozygous Grin2a knock out mice 64 . Since MD is bidirectionally connected with the prefrontal cortex and Grin2a is highly expressed in this area, one possibility could be that lack of NR2A impaired the functional inputs from the prefrontal cortex to MD and thus affecting the functional maturation of MD during development 37,53,64,65 .…”

Disorganized Inhibitory Dynamics and Functional Connectivity in Hippocampal area CA1 of 22q11.2 Deletion Mutant Mice

“…(C) Pearson correlation coefficients of interneuron activity and velocity for all tested interneuron subtypes (WT: n = 97 AACs, 53 PVBCs, 194 SomCs, 115 IvCs/NGFCs, and 44 CCKCs from n = 6 mice, Df(16)A +/- : 46 AACs, 87 PVBCs, 181 SomCs, 72 IvCs/NGFCs, and 14 CCKCs from n = 5 mice). WT: one-way ANOVA (p < 10 26 ), Df(16)A +/- : one-way ANOVA (P < 10 10 ) with post hoc Tukey’s range test corrected for multiple testing. (D) Peristimulus time histograms (PSTHs) of average traces during Run-Start and Run-Stop events, Left: WT, Right: Df(16)A +/- .…”

Schizophrenia: a role for Grin2A?

“…Thus far, genome-wide association studies (GWASs) have identified many common variants linked to schizophrenia; most of these show small effects on disease risk. Now, in a study that could represent an important step forward, a research team headed by Morgan Sheng presents new data that may indict Grin2A as a major contributor to schizophrenia (Farsi and others 2023). Grin2A encodes the GluN2A subunit of the NMDA receptor and has been linked to schizophrenia in multiple genetic studies and by GWAS fine-mapping and, on this basis, has been considered a risk factor for schizophrenia.…”

“…The new article builds on these findings and on the observation that heterozygous loss-of-function mutations in Grin2A substantially increase the risk of schizophrenia. In this new study, Farsi and others (2023) use a powerful set of transcriptomic, proteomic, and behavioral analyses to show that mice lacking Grin2a model multiple features of schizophrenia. These mice display large-scale gene expression changes across multiple brain regions; notably, these changes not only occur in excitatory and inhibitory neurons but also are seen in astrocytes (which showed abnormal cholesterol biosynthetic pathways) and oligodendrocytes (which displayed changes in pathways related to the cytoskeleton, neuronal ensheathment and myelination, and changes in pathways related to biosynthesis of chondroitin sulfate, which is enriched at perineural nets).…”

“…In addition to providing a new and powerful animal model that adds to the evidence underlying neurotransmitter theories of schizophrenia, this comprehensive multiomics study suggests that processes such as myelination, steroid/cholesterol biosynthesis, and perineuronal net formation may contribute to the pathobiology of schizophrenia. This animal model and the comprehensive analysis by Farsi and others (2023) represent a step forward that may bring us closer to understanding this enigmatic disorder.…”