Biochemical Mechanisms that Control the Effects of RhoA Small GTPase Signaling on Synaptic Stability and Cognition

Abstract

Dendritic spines are the site of most excitatory connections in the brain. Small GTPases act as binary switches that link cell surface receptors to persistent modifications in the morphogenesis of dendritic spines. Small GTPases are active when bound to GTP and inactive when GDP bound. The direct activation of small GTPases is accomplished by guanine nucleotide exchange factors (GEFs). The small GTPase RhoA, is enriched in dendritic spines and its activation can destabilize the actin cytoskeleton within spines reducing dendritic spine stability. Rodent studies suggest that excessive RhoA signaling causes cognitive impairment in part via its ability to reduce dendritic spine density in forebrain neurons. Despite the broad therapeutic potential of targeting the RhoA pathway as a means of enhancing cognition, the specific biochemical mechanisms that control its activity in neurons remain largely unknown. PDZ‐RhoGEF is a RhoA‐specific guanine nucleotide exchange factor that shows an unusually potent ability to activate RhoA. We show that PDZ‐RhoGEF destabilizes dendritic spines in cortical neurons and causes cortical‐dependent cognitive impairment. Ongoing studies are extending this analysis to determine if PDZ‐RhoGEF is similarly important for activity‐mediated remodeling of dendritic spines after NMDA receptor activation. Despite the importance of PDZ‐RhoGEF to synaptic and cognitive phenotypes, owing to a lack of studies, minimal is known about the biochemical mechanisms that regulate PDZ‐RhoGEF. Our recent findings indicate that PDZ‐RhoGEF activity and cellular localization is controlled by its interaction with the DISC1 scaffolding‐like protein, such that DISC1 helps localize PDZ‐RhoGEF to cellular membranes yet inhibits PDZ‐RhoGEF’s ability to activate RhoA. Experiments utilizing structured illumination microscopy are being conducted to further assess the functional consequences of the interaction between PDZ‐RhoGEF and DISC1 in neurons, and in particular, within dendritic spines. We theorize that the knockdown of DISC1 in neurons will result in the improper synaptic localization of PDZ‐RhoGEF with a concomitant increase in PDZ‐RhoGEF‐mediated RhoA activity. Collectively, these findings identify PDZ‐RhoGEF as a potent regulator of synaptic stability and cognition and highlight a previously unrecognized involvement for DISC1 in controlling RhoA activity via PDZ‐RhoGEF.