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
AUTHORS (23)
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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