Researchers studying a protein that is strongly linked to the psychiatric disorder are the first to determine the protein’s function, tracing it to a structure in the hippocampus called the dentate gyrus.
From USC Dornsife Magazine
By Darrin S. Joy
February
10, 2022 -- 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.
- Schizophrenia
affects about 20 million people around the globe.
- Symptoms
include hallucinations, delusions, flat affect (lack of emotional
expression), loss of a sense of personal identity, and memory loss.
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.
- Scientists
have recently discovered that mutations inhibiting SAP97 function can give
rise to schizophrenia.
- These
mutations are linked to a 40-fold increase in the risk of developing
schizophrenia — the largest increase in risk documented for any mutation
to date.
- The
normal function of SAP97 — that is, what it normally does and where it
does it in the brain — has remained elusive for many years.
- Not
knowing how or where the protein works has also kept a veil over why
mutations in SAP97 would lead to schizophrenia.
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.
- Glutamatergic
signaling is an important way neurons communicate with each other that
involves neurons releasing the neurotransmitter glutamate onto neighboring
neurons.
- Experiments
up to now have failed to show that SAP97 plays any significant part in
regulating glutamatergic signaling in the brain.
- The
lack of evidence for SAP97 function in regulating communication between
neurons has frustrated scientists, given the growing evidence of the
protein’s connection to schizophrenia.
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.
- The
dentate gyrus is located within the hippocampus.
- It
controls contextual episodic memory — the conscious recollection of life
experiences that includes what happened along with when and where it
happened.
- Contextual
episodic memory is often altered in those with schizophrenia, and such
alterations may contribute to the development of other symptoms associated
with the disorder.
Studying rats with damaged SAP97, the
researchers looked for changes in activity in the dentate gyrus — and they
found them.
- Neurons
in the dentate gyrus with reduced SAP97 function showed extremely large
increases in glutamatergic signaling.
- The
increase in signaling with mutated SAP97 suggests the protein normally
helps dampen glutamatergic signaling specifically within the dentate
gyrus.
- The
large increases in glutamatergic signaling in the dentate gyrus caused by
reduced SAP97 function also produced significant deficits in contextual
episodic memory in rodents — a hallmark of schizophrenia.
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.
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