In the process of solving a decades-long mystery about a particular protein, scientists have identified a specific location in the brain where schizophrenia may originate.
The news: Despite the identification of many genes that show some link to schizophrenia, identifying a part of the brain that is likely responsible for the disorder with a high level of certainty has proven to be extremely difficult — until now.
Why it’s important: Knowing where to look and what to look for could help identify those at risk of schizophrenia before the disorder strikes and might lead to new diagnostic, preventive and treatment measures.
A protein without a role
The study , led by researchers at the USC Dornsife College of Letters, Arts and Sciences and published online Feb. 10 in Nature Communications , centers on a protein called synapse-associated protein 97, or SAP97, that is found in neurons in the brain.
From the principal researcher: “Reduced SAP97 function may very well give rise to the largest increase in schizophrenia risk in humans that we know of, but the function of SAP97 has been a total mystery for decades. Our study reveals where SAP97 functions in the brain and shows exactly what schizophrenia-associated mutations in this protein do to neurons.”
— Bruce Herring , assistant professor of biological sciences at USC Dornsife
A deeper look
SAP97 belongs to a family of proteins that regulate glutamatergic signaling between neurons and influence how memories are created and stored.
What they did: With no SAP97 activity apparent in traditionally studied brain regions, Herring and his team chose to look at a different region of the brain that has been theoretically linked to schizophrenia, called the dentate gyrus.
Studying rats with damaged SAP97, the researchers looked for changes in activity in the dentate gyrus — and they found them.
A scientific first: The results are the first to confirm where in the brain SAP97 is active and to directly link alterations in dentate gyrus function to the development of schizophrenia.
What’s next?
In future studies, Herring and his team plan to look for SAP97 activity in other areas of the brain.
They will also determine whether schizophrenia-linked mutations in other proteins produce similar increases in glutamatergic signaling in the dentate gyrus.
Their ongoing work will significantly aid the development of more effective treatment strategies for this historically enigmatic disorder.
Authors and funding
In addition to corresponding author Herring, additional researchers on the study are USC Dornsife graduate students Yuni Kay (first author), Linda Tsan, Chen Tian and Anna Pushkin; USC Dornsife postdocs Léa Décarie-Spain and Anastasiia Sadybekov; Vsevolod Katritch, associate professor of quantitative and computational biology and chemistry, and Scott Kanoski, associate professor of biological sciences; and former USC Dornsife postdoc Elizabeth Davis.
The study was funded by National Institute of Mental Health grant number MH103398, National Institute of Neurological Disorders and Stroke grant number NS112480 and the Simons and McKnight Foundations.
Nature Communications
Experimental study
Animals
Schizophrenia-associated SAP97 mutations increase glutamatergic synapse strength in the dentate gyrus and impair contextual episodic memory in rats
10-Feb-2022
The authors declare no competing interests.