New Northwestern Medicine research could enhance scientists’ understanding of schizophrenia and other psychiatric disorders. In a study published in the Proceedings of the National Academy of Sciences (PNAS), investigators used a drug that targets a network hub of schizophrenia-related genes in mouse model neurons to reverse the appearance of a phenotype traditionally associated with the disease.
The team focused on the dendrites, or receptive fields, of mouse model neurons.
“What we found was that the dendrites of neurons from the microduplication mice were more branched,” said co-author Peter Penzes, PhD, professor of Physiology and Psychiatry and Behavioral Sciences.
Mice that had a microduplication, or genetic copy number variation, at the 16p11.2 gene location had longer dendrites, meaning their brain cells were hyperconnected. Microduplication at that gene location has previously been associated with psychiatric disorders like schizophrenia and autism spectrum disorder.
In this study, scientists decided to locate the gene that could reverse this dendrite overgrowth, rather than trying to find the genes responsible for causing the alteration. They used network analysis to identify important nodes in the protein-protein network of genes related to schizophrenia, including 16p11.2.
“This is probably the first study in this field where network biology was used to identify a target for correcting disease-related alteration,” Penzes said.
Penzes and his co-authors found that the most highly-connected node in the molecular network was MAPK3, a kinase that encodes ERK1 MAP kinase. By targeting this node with an inhibiting drug, the investigators reversed the changes in the dendrites, keeping them from becoming hyperconnected, and suggesting a potential approach for future treatment.
“We think that MAPK3 is a driver of reversal of the phenotype,” Penzes said. “It may not be what causes this dendritic alteration, but clearly if we inhibit it, it reverses the phenotype.”
This research was supported by National Institute of Mental Health grants MH071316, MH097216, MH071616, MH084803 and R21MH102685 and a Swiss National Science Foundation Early Postdoc Mobility Fellowship.
