In solving a decades-long mystery, scientists discover that schizophrenia may originate in the brain

For the first time, researchers studying a protein closely linked to mental illness have determined the protein's function, tracing it to a structure in the hippocampus called the dentate gyrus
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In the process of unraveling a decades-long protein mystery, scientists have identified a specific location in the brain where schizophrenia may originate
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Although many genes linked to schizophrenia have been identified, it has been extremely difficult to pinpoint the parts of the brain that may be involved in schizophrenia -- until now
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Why it matters: Knowing where to look and what to look for can help identify those at risk for schizophrenia before it strikes and could lead to new diagnoses, prevention, and treatments
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• About 20 million people worldwide suffer from schizophrenia
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• Symptoms include hallucinations, delusions, flat affect (lack of emotional expression), loss of personal identity, and memory loss
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inactive protein

The study, led by researchers at the USC Dornsife College of Arts and Sciences, was published online Feb.
10 in the journal Nature Communications
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The research centers on a protein called synapse-associated protein 97 (SAP97), which is found in neurons in the brain
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• Scientists recently discovered that mutations that inhibit the function of SAP97 cause schizophrenia
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• These mutations increased the risk of schizophrenia by a factor of 40—the largest increase in risk of any mutation recorded to date
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• The normal function of SAP97—that is, its normal function and location in the brain—has been elusive for years
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• Since it is not known how the protein works, it is also not known why mutations in SAP97 cause schizophrenia
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"Decreased SAP97 function is likely the greatest cause of increased risk of schizophrenia in humans that we know of, but the function of SAP97 has been a mystery for decades
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Our study sheds light on the role of SAP97 in the brain and shows precisely The effects of this schizophrenia-associated protein mutation on neurons were investigated
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—Bruce Herring, assistant professor of biological sciences at USC Dornsife

a deeper view

SAP97 belongs to a family of proteins that regulate glutamate signaling between neurons, affecting how memories are produced and stored
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• Glutamate signaling is an important pathway by which neurons communicate with each other and involves neurons releasing the neurotransmitter glutamate to neighboring neurons
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• So far, experiments have not demonstrated that SAP97 plays any important role in regulating glutamate signaling in the brain
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• The lack of evidence for SAP97's function in regulating interneuron communication has frustrated scientists as evidence mounts that the protein is involved in schizophrenia
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What they did: With no apparent SAP97 activity in the traditionally studied brain region, Herring and his team chose another brain region theoretically linked to schizophrenia -- the dentate gyrus
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• The dentate gyrus is located in the hippocampus
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• It controls situational episodic memory — the conscious recall of life experiences, including what happened and when and where it happened
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• Contextual episodic memory is often altered in people with schizophrenia, and this alteration may lead to the development of other symptoms associated with the disorder
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When studying mice with impaired SAP97, the researchers looked for changes in dentate gyrus activity—and they found it
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• Neurons with reduced SAP97 function in the dentate gyrus exhibited greatly increased glutamate signaling
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• The increase in mutated SAP97 signaling suggests that this protein normally helps suppress glutamate signaling within the dentate gyrus
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• The massive increase in glutamate signaling in the dentate gyrus, caused by reduced SAP97 function, also led to marked deficits in contextual episodic memory in rodents—a hallmark of schizophrenia
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A first discovery in science: The findings demonstrate for the first time where in the brain SAP97 is active and directly link changes in dentate gyrus function to the development of schizophrenia
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What's next?

In future studies, Herring and his team plan to look for SAP97 activity in other areas of the brain
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They will also determine whether mutations in other proteins associated with schizophrenia produce similar glutamate signaling in the dentate gyrus
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Their ongoing work will greatly aid in the development of more effective therapeutic strategies to treat this historically mysterious disease
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references:

“Schizophrenia-associated SAP97 mutations increase glutamatergic synapse strength in the dentate gyrus and impair contextual episodic memory in rats” by Yuni Kay, Linda Tsan, Elizabeth A.
Davis, Chen Tian, ​​Léa Décarie-Spain, Anastasiia Sadybekov, Anna N.
Pushkin, Vsevolod Katritch, Scott E.
Kanoski and Bruce E.
Herring, 10 February 2022,  Nature Communications .

DOI: 10.