Abstract
By some estimates, slightly over 1% of Americans have schizophrenia. The worldwide number suggested by the World Health Organization is close to 20 million, but this may be an underestimate because many cases do not come to medical attention. There is also an immense impact on families. Yet despite its importance as an unmet medical need and despite intense study, the genetic, molecular, and cellular substrates for schizophrenia remain incompletely understood. Environmental as well as factors both appear to contribute, but an estimated heritability of schizophrenia of 60% to 80% underscores the substantial role of genetics in the pathobiology of this disorder. Thus, there has been a major effort to understand its genetics. 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). They also display prefrontal cortex hypoactivity and hyperactivity in the hippocampus and striatum. There was also hypersensitivity to amphetamine-induced hyperlocomotion in these mice. Intriguingly, the levels of glutamatergic receptor signaling proteins at synapses were reduced. Notably, these changes were accompanied by changes in striatal dopamine signaling, an observation that is especially interesting in the context of the classical “dopamine hypothesis” of schizophrenia. Finally, these mice exhibited abnormal patterns of locomotor activity, opposite to the changes seen with antipsychotic drugs. 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.