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

Neurons Proteomics Mice Disease Models, Animal Dopamine Animals Brain Prefrontal Cortex Neuroglia Receptors, N-Methyl-D-Aspartate 3. Good health
DOI: 10.1016/j.neuron.2023.08.004 Publication Date: 2023-08-31T15:45:31Z
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 the NMDA receptor, greatly increase risk SCZ. By transcriptomic, proteomic, and behavioral analyses, we report that Grin2a mutant mice show (1) large-scale gene expression changes across multiple brain regions neuronal (excitatory inhibitory) non-neuronal cells (astrocytes oligodendrocytes), (2) evidence hypoactivity prefrontal cortex (PFC) hyperactivity hippocampus striatum, (3) an elevated dopamine signaling striatum hypersensitivity to amphetamine-induced hyperlocomotion (AIH), (4) altered cholesterol biosynthesis astrocytes, (5) reduction glutamatergic receptor proteins synapse, (6) aberrant locomotor pattern opposite induced by antipsychotic drugs. These findings reveal potential pathophysiologic mechanisms, provide support for both "hypo-glutamate" "hyper-dopamine" hypotheses SCZ, underscore utility Grin2a-deficient as genetic
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