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Gyrus dentatus

Origin of schizophrenia in the brain – gene mutation alters ‘gatekeeper’ and increases risk of schizophrenia by 40-fold

Although millions of people around the world suffer from schizophrenia, it was previously not clear where it originated in the brain. Now the researchers can pinpoint the region – located in the hippocampal substructure, which is important for memory. There, a genetic mutation causes excessive activity of glutamate receptors and thus increases the risk of developing schizophrenia by a factor of 40.

hallucinationsParanoia, disorders of self-consciousness, and I – awarenessSchizophrenia: About 20 million people worldwide suffer from schizophrenia. However, the causes of this mental illness have not yet been clarified, even if genetic predisposition is considered an important risk factor. Indeed, some risky genes for schizophrenia have already been identified, but how and where they function is unknown.

SAP97 Jin Secret

This also applies to the risk gene with the greatest effect: SAP97. Studies show that defects in this gene increase the likelihood of developing schizophrenia by a factor of 40. “The reduced function of SAP97 thus causes the largest increase in schizophrenia risk known to date in humans,” says senior author Bruce Herring of the University of Southern California. “But the exact function of SAP97 has remained a mystery for decades.”

Problem: SAP97 is known to belong to a group of proteins essential for synapse function and which influence the response to the neurotransmitter glutamate. To date, however, no changes in brain metabolism of this neurotransmitter have been found in the defective SAP97 gene vector. It also remained unclear where this defective gene becomes noticeable in the brain.

Targeting the dentate gyrus

But Herring’s team has now, for the first time, succeeded in finding the working site of SAP97 – and at the same time, the possible origin of schizophrenia. The starting point in their study was the question of whether the dentate gyrus might play a role in schizophrenia. This infrastructure in the hippocampus is the entry point into the brain’s memory center and acts as a kind of gatekeeper for incoming stimuli and information.

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This particular gatekeeper function appears to be impaired in schizophrenia, so it has long been suspected that the dentate gyrus plays a role in this condition. For their study, first author Yoni Kai and their team examined what happens in the brain of mice when the SAP97 gene operates only to a limited extent.

Gene defect leads to ‘pyloric’ overstimulation

It turns out that if the SAP97 gene is defective, then the synapses in the dentate gyrus are overstimulated. As a result, neurons fire with similar intensity and frequency as if the synapses had been flooded with large amounts of the neurotransmitter glutamate. In contrast to other parts of the hippocampus, SAP97 appears to play an important role as an inhibitory regulator of the glutamate response, particularly in the gatekeeper of the memory center, the team reported.

But is this effect sufficient to induce schizophrenia? “Studies show that many of the core symptoms of schizophrenia, such as hallucinations, disorganization, and ego disturbances, result from disturbances in the processing of contextual information in episodic memory formation,” Kay and colleagues explain.

Typical symptoms

The dentate gyrus and SAP97 protein seem to play an important role in memory formation, as experiments with mice have shown: if the SAP97 gene is defective in animals, processing of context information and stimuli during learning is also disrupted. “This demonstrates that disruption of SAP97 function in the dentate gyrus is sufficient to cause behavioral defects, as has also been observed in subjects with schizophrenia,” the researchers wrote.

According to the team, the results indicate that schizophrenia is closely related to gatekeeper function in the hippocampus. So the origin of this mental illness can lie in this brain region. The scientists now want to investigate whether other genes with a lower risk of schizophrenia might also impair the function of the dentate gyrus.

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We hope for more targeted therapies

Kay and her colleagues hope that if this region of the brain is confirmed to be the origin of schizophrenia, it may also help develop more effective treatments against the disease and its neurological causes. (Nature Communications, 2022; doi: 10.1038/s41467-022-28430-5)

Source: University of Southern California