Identification of ARHGEF11 (PDZ-RhoGEF) as an in vivo regulator of synapses and cognition.

Given the influence of cognitive abilities on life outcomes, there is inherent value in identifying genes involved in controlling learning and memory. Further, cognitive dysfunction is a core feature of many neuropsychiatric disorders. Here, we use a combinatory in silico approach to identify human gene targets that will have an especially high likelihood of individually and directly impacting cognition. This broad and unbiased screen led to the specific identification of ARHGEF11, which encodes PDZ-RhoGEF. PDZ-RhoGEF is a largely RhoA-specific activator that is highly enriched in dendritic spines, and recent work identified hyperexpression of PDZ-RhoGEF in the prefrontal cortex of bipolar disorder subjects, a disease characterized by an early emergence and persistence of broad scope cognitive dysfunction. Here, we characterize the effects of PDZ-RhoGEF on synaptic and behavioral phenotypes, and we identify molecular and biochemical mechanisms that control PDZ-RhoGEF's expression, synaptic spatial localization, and enzymatic activity. Importantly, our identified direct regulators of PDZ-RhoGEF (miR-132 and DISC1) have themselves been repeatedly implicated in controlling cognitive phenotypes in humans, including those caused by several neuropsychiatric disorders. Taken together, our findings indicate that PDZ-RhoGEF is a key convergence point among multiple synaptic and cognition-relevant signaling cascades with potential translational significance.