A collaborative study published last week in Neuron has described a genetically valid mouse model to study the mutations that give rise to schizophrenia in humans. Researchers have identified both common and rare mutations associated with the disease and present a useful animal model for further study.
A New Way to Study Schizophrenia
Schizophrenia has an estimated heritability of 60-80%. However, our understanding of the mechanisms of the disease has been significantly impeded by a lack of genetically valid animal models.
A 2022 landmark genetic study undertook schizophrenia whole-exome sequencing meta-analysis (SCHEMA), revealing 10 genes that researchers are highly confident are associated with the disease at exome-wide significance – referred to as SCHEMA genes. SCHEMA variants are dominated by loss-of-function mutations, implying that having just one mutated copy of these genes (heterozygous loss) is enough to increase the risk of the disease. This suggests that these genes play a crucial role in schizophrenia development.
This study builds upon last year’s findings by developing a genetically valid animal model that presents as a valuable resource to decode the mechanisms of the disabling mental illness.
Triggers Inside and Outside of the Brain
Researchers from MIT and the Broad Institute of MIT and Harvard used the new model to examine the effects of a loss-of-function mutation in one of ten SCHEMA genes. The gene in question, GRIN2A, encodes subunits of NMDAR receptors and loss-of-function mutations in this gene significantly increase the risk of schizophrenia. Despite this, they found that transcriptomic changes in NMDAR receptors are poorly or even anti-correlated with the same brain region in the mouse models. In fact, single-nucleus RNA sequencing shows that a wide range of cell types across the brain are affected by mutations in the GRIN2A gene.
Effective antipsychotic drugs antagonistically target the D2 dopamine receptor, hence hyperdopaminergic signalling is a long-standing hypothesis for the pathophysiology of schizophrenia. Researchers confirmed this theory, with Grin2a+/- mouse models showing evidence of hyperdopaminergic signalling in parts of the brain (Fig. 1)
In addition, multi-omics data uncovered unexpected mechanisms that might also play a role in the development of the disease. These include altered metabolism, protein translation, myelination, steroid/cholesterol biosynthesis, RNA processing and even the involvement of non-neural cells (astrocytes and oligodendrocytes).
Figure 1 | Visualisation of the effects of loss-of-function of the Grin2a+/- gene in mouse models. Adapted from Farsi et al., 2023.
Paving the Way for Better Treatment
The study contributes to the effort to acquire a comprehensive understanding of the pathophysiology of schizophrenia. This will inform the development of more effective treatments with less unwanted side effects and hopes to improve the quality of life of those living with the disease.
Furthermore, the identification of genes associated with increased risk of schizophrenia will pave the way for future genetic testing.
“Finally, we have an animal model with human-genetic validity and robust neurobiological overlap with human patients that can help scientists learn how existing treatments work and potentially help identify new ones… We hope others will utilize this rich data resource that we’ve shared for future mechanistic and therapeutics studies and to explore the roles of less studied mechanisms such as cholesterol dysregulation in schizophrenia pathophysiology.” commented first author of the study Zohreh Farsi, Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard.