PROJECT SUMMARY
Cognitive abilities have a profound impact on life outcomes. As such, there has been much scientific interest in
identifying genes that are critical for regulating cognitive phenotypes. The miR-132 microRNA is among the few
studied microRNAs that impacts learning and memory in rodents, is dysregulated in multiple human disorders
typified by cognitive impairment, and regulates synaptic structure and function. Human genome wide association
studies (GWAS) have identified numerous genes of potential relevance to general cognitive function, yet a
challenge is identifying which genes, among the many, are likely to have direct effects on learning and memory.
Genes that are targets of miR-132, and that have also been identified in GWAS of human cognitive function,
could have a high likelihood of directly impacting learning and memory. The overlay of empirically identified high
probability miR-132 gene targets with a list of genes that exhibit genome-wide significant association with human
cognitive abilities lead to the identification of two genes, one of which is ARHGEF11. ARHGEF11 encodes PDZ-
RhoGEF, a guanine nucleotide exchange factor (GEF) for the RhoA small GTPase. Within the brain, PDZ-
RhoGEF is most highly detected in the cerebral cortex, including the prefrontal cortex (PFC). PDZ-RhoGEF is
enriched in the dendrites and dendritic spines of pyramidal neurons, with minimal detectable expression in glia.
Despite being among the most potent known activators of RhoA, no studies have investigated the functions of
PDZ-RhoGEF in the brain. One overarching theory guiding this proposal is that PDZ-RhoGEF is a critical
regulator of dendrite and dendritic spine stability, and that it also regulates synaptic function, neuronal
engagement and cognition. A second overarching theory guiding this proposal is that PDZ-RhoGEF is a
previously unrecognized component of multiple signaling pathways of known importance for controlling synaptic
and cognitive phenotypes. Aim 1 will use viral-mediated gene transfer to determine if increased levels of PDZ-
RhoGEF in the prefrontal cortex affects synaptic structure, synaptic function, neuronal engagement, and
cognition in a manner that requires RhoA activation. Aim 2 will determine if the effects of altered miR-132
expression on dendritic spine stability and cognition are due, at least in part, to miR-132's ability to control levels
of PDZ-RhoGEF. As part of the experimental design of Aim 2, we will also simultaneously determine the effects
of PDZ-RhoGEF knockdown in the mouse prefrontal cortex on baseline dendritic spine and cognitive
phenotypes. Aim 3 will use enzyme activity assessments, super resolution synaptic imaging, and viral gene
transfer to characterize the physical and functional interaction between PDZ-RhoGEF and the scaffolding-like
protein DISC1. As part of Aim 3, we will determine if the effects of DISC1 loss on synapse destabilization and
cognitive impairment are due to excessive PDZ-RhoGEF activity. If our hypotheses are correct, these studies
could identify a previously unrecognized role for PDZ-RhoGEF in controlling synaptic and cognitive phenotypes
via multiple signaling pathways, and illuminate RhoA signaling as a target for future therapeutics.
