Novel gene therapy curbs schizophrenia symptoms

Jennifer Donegan, Ph.D.
Jennifer Donegan, Ph.D., of UT Health San Antonio

Highlight:  An experimental treatment tested at UT Health San Antonio reduced delusions and hallucinations while improving cognitive skills in rats.

Jennifer Donegan, Ph.D., and colleagues at UT Health San Antonio describe a novel, experimental approach to treating schizophrenia in the journal Nature Communications (published June 27). If developed into a human therapy, the new strategy could be a significant improvement on existing drugs that don’t treat all types of schizophrenia symptoms and cause undesirable side effects, researchers said.

The San Antonio team is targeting the hippocampus—a center of learning and memory in the brain. Dysfunction of the hippocampus is associated with many psychiatric and neurological diseases including schizophrenia.

Human research has shown that the hippocampus is hyperactive in schizophrenia, Dr. Donegan said. It is like a car engine that idles too high in park.

Donegan and Lodge with hippocampus art
Dr. Jennifer Donegan looks at an artist’s rendering of the hippocampus with her research mentor, Dr. Daniel Lodge, Department of Pharmacology at UT Health San Antonio.

“Activity in the hippocampus is primarily controlled by a balance between excitatory and inhibitory neurons, which are cells of the central nervous system,” Dr. Donegan said. “We think that the hyperactivity observed in schizophrenia patients is caused by a loss of inhibitory cell function.”

Results

Studying rats that model schizophrenia, the team used gene therapy techniques to increase the inhibitory neurons in the hippocampus. This not only reduced delusions and hallucinations, but also improved cognitive function in the rodents.

“The main finding is that increasing inhibitory function in the hippocampus can improve multiple schizophrenia symptoms and may be a more effective treatment strategy than the drugs we currently have available for schizophrenia,” Dr. Donegan said.

“We also identified the neural pathways from the hippocampus that are responsible for different symptom types in this disorder,” she said.

The toll of this disorder

The prevalence of schizophrenia in the United States and internationally is difficult to measure for a variety of reasons. Various studies that included household-based surveys, clinical diagnostic interviews and medical records have placed the estimated prevalence in the U.S. at between 0.25% and 0.64%, according to the U.S. National Institute of Mental Health (NIMH). This is approximately 800,000 to 2 million Americans.

Schizophrenia is one of the 15 leading causes of disability worldwide, according to the NIMH.

Delusions and hallucinations are classified as being in one category of symptoms, while social withdrawal and lack of emotion are in another category, and low attention and memory are in another. Existing drugs do not improve the second and third categories.

Some patients experience drowsiness, weight gain, nausea and other side effects with current treatment.

“Social withdrawal, low memory and other symptoms can make it difficult to participate in day-to-day activities, including holding down a job and maintaining relationships,” Dr. Donegan said.

Acknowledgments:

This research project led to a “pathway to independence” K99/R00 grant award for Dr. Donegan from the National Institutes of Health. With this funding, Dr. Donegan will continue to study the anatomical basis by which the hippocampus regulates different symptom domains in schizophrenia, said her research mentor, Daniel Lodge, Ph.D., associate professor of pharmacology at UT Health San Antonio.

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