Schizophrenia gene mutation causes many changes in the mouse brain

Good news! Are we finally getting closer to identify the causes of severe mental health disorders! I bet, applying AI will help too!

"Researchers have identified common and rare gene mutations that increase risk for schizophrenia. Yet it’s unclear what biological mechanisms go awry in the brain to cause psychosis and other disabling symptoms, due in part to a lack of valid animal models to study in the lab.

Now, scientists ... have taken a thorough, unbiased look at an animal model that carries a rare genetic mutation that greatly increases the risk of schizophrenia in humans. The researchers examined multiple brain regions and cell types in mice lacking the Grin2a gene, which encodes a type of glutamate receptor involved in communication between neurons. They observed wide-ranging changes in gene expression, brain cell activity, cell signaling, synapse protein composition, and animal behavior. ...

A 2022 landmark genetic study ... researchers identified rare mutations in 10 genes that strongly increase risk of schizophrenia. One of these is the GRIN2A gene, which encodes a subunit of a protein complex called the NMDA receptor. This receptor binds to the neurotransmitter glutamate and scientists have long speculated that impaired glutamate signaling contributes to schizophrenia, but the biological role of the NMDA receptor in the disorder was still unclear.

In the current study, ... set out to systematically characterize the effects of the Grin2a mutation in mice. In humans, the mutation effectively breaks one copy of the gene (a mechanism they recently confirmed), so the team generated a so-called “heterozygous” mouse model in which one copy of the Grin2a gene is disrupted, leaving one working copy. ...

Remarkably, their analysis also supported another long-standing hypothesis, centered on dopamine. Researchers have suspected that excessive dopamine signaling is partly to blame in schizophrenia, because medicines that block dopamine receptors are effective in reducing psychotic symptoms. In a brain region called the striatum, the team found evidence for unrestrained dopamine signaling, including a striking increase in expression of the dopamine receptor gene Drd2, which is the target of most antipsychotic drugs. The scientists also found reduced levels of an enzyme that degrades dopamine, providing further evidence for dopamine’s role in the disorder. ..."

From the highlights and abstract:

"Highlights

• Mice lacking Grin2a, a human risk gene, model several aspects of schizophrenia

• Grin2a+/− mice show prefrontal cortex hypoactivity and hippocampal hyperactivity

• Hyperdopaminergic state in striatum and amphetamine hypersensitivity in Grin2a+/− mice

• Astrocytes, oligodendrocytes, and diverse neuronal types are affected in Grin2a+/− mice

Summary

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."

Schizophrenia gene mutation causes many changes in the mouse brain | Broad Institute A study of a genetic mouse model of schizophrenia supports two long-debated hypotheses, and unveils additional new clues about the biological roots of the disorder.

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

Graphical abstract: