Description:

"Altered Cortical Expression of a RhoA-specific Guanine Nucleotide Exchange Factor in Bipolar Disorder Causes Altered Synaptic Stability and Cognitive Dysfunction "

Bipolar disorder is characterized by fluctuations in mood, including mania/hypomania and depressive episodes, and a large percentage of subjects also experience psychosis. Further, cognitive impairment of a level considered clinically significant occurs in the majority of bipolar disorder subjects. Multiple studies have identified a reduction in the density of dendritic spines on pyramidal neurons of the prefrontal cortex of bipolar disorder subjects, and this loss of synapses is theorized to contribute, at least in part, to the cognitive impairments of this disorder. Our recent findings identified an increase in the protein levels of a RhoA-specific activator, PDZ-RhoGEF, in the prefrontal cortex of male and female bipolar disorder subjects. Recently, we have employed an in vivo reverse translational approach to determine if increased prefrontal cortical PDZ-RhoGEF expression is sufficient to give rise to the synaptic destabilization and cognitive impairments characteristic of bipolar disorder subjects. Our findings indicate that PDZ-RhoGEF reduces synaptic stability and impairs spatial working memory and spatial recognition memory. Recent efforts have aimed at characterizing the molecular mechanisms that control PDZ-RhoGEF expression in the cortex and the biochemical mechanisms that control PDZ-RhoGEF’s access to RhoA. These mechanistic studies have revealed a role for the miR-132 microRNA in directly controlling PDZ-RhoGEF levels and the DISC1 synaptic scaffolding protein in controlling PDZ-RhoGEF’s synaptic localization and enzymatic activity. Importantly, miR-132 and DISC1 have been heavily implicated in controlling human cognitive phenotypes. Overall, these studies identify PDZ-RhoGEF as a critical component of multiple signaling cascades with potential relevance to cognition in both non-diagnostic populations and in bipolar disorder subjects.

Thursday October 5, 2023  
CAN Seminar Series 
2:00 PM - 3:00 PM  
Location: Ward 5-230

Michael Cahill, Ph.D.
Assistant Professor 
Department of Comparative Biosciences 
University of Wisconsin at Madison