Researchers at Vanderbilt have been able to alter mouse behavior by silencing gene expression in interneurons, distinct populations of nerve cells that are the main regulators of brain circuits.
Interneurons can be thought of as the “building blocks” to impact behavior. Researchers found that changing the expression of a gene in one interneuron population had the exact opposite molecular and behavioral effect compared to changing the same gene in another.
“Variations in these interneuron populations are not only important in the context of schizophrenia and disease, but in defining our personalities through behavior and activity in response to stimuli,” said senior author Karoly Mirnics, M.D., Ph.D., James G. Blakemore Professor of Psychiatry.
Schizophrenia is a mental disorder characterized by hallucinations, delusions and disorganized thinking, affecting an estimated one out of every 100 adults.
It is complex, involving different combinations of possibly hundreds of gene mutations as well as environmental factors. With multiple deficits in a patient, a one-size-fits-all approach to treatment is less than ideal.
Schizophrenia is a uniquely human, complex brain disorder, and a true rodent model of this disease does not and will not exist, according to Mirnics.
But it can be determined how these different interneuron populations regulate certain aspects of behavior in mouse models, providing insight into the underlying roles of these “anatomical building blocks of behavior.”
The researchers studied “transgenic” mice, in which the expression of a certain gene had been “turned off” in specific interneuron populations, and then examined the molecular and behavioral consequences of this manipulation.
A mass spectrometry technique pioneered at Vanderbilt called MALDI-IMS enabled researchers in this study to “see” how changes in gene expression affected levels of proteins important in brain signaling and function.
Until now, it was known that interneurons controlled complex behaviors and synchronized neuronal networks, but there was a limited understanding of the types of behaviors that were mediated by specific interneuronal subclasses.
This finding, recently reported in the journal Molecular Psychiatry, could have broad implications for improved and more targeted therapies for complex brain conditions like autism, epilepsy, bipolar disorder and schizophrenia.
“We are systematically targeting interneuron subpopulations,” Mirnics said. “If we can modulate and control these individual cell types and achieve predicted results in mice, we could one day translate this to humans.
“Ultimately, that’s what will take us to personalized medicine, where the specific interneuronal deficit in a particular patient might help us tailor the treatment,” he said.
The research was made possible by the expertise of Vanderbilt’s Transgenic Mouse/ESC Shared Resource, Murine Neurobehavioral Laboratory and the Protein Core of the Mass Spectrometry Research Center.
Support was provided by National Institutes of Health grant MH967234, the Vanderbilt Kennedy Center and a Vanderbilt Brain Institute Scholar Award earned by first author Martin J. Schmidt, a graduate student in Mirnics’ lab.
— Elizabeth Conrad is a graduate student in Molecular Physiology and Biophysics
