RhoGTPases at the synapse: An embarrassment of choice

Activity-dependent modifications in the strength of excitatory synapses are considered to be major cellular mechanisms that contribute to the plasticity of neuronal networks underlying learning and memory. Key mechanisms for the regulation of synaptic efficacy involve the dynamic changes in size and number of dendritic spines, as well as the synaptic incorporation and removal of AMPA-type glutamate receptors (AMPAr). As key regulators of the actin cytoskeleton, the Rho subfamily of GTP-binding proteins play a critical role in synaptic development and plasticity. They shuttle between the active GTP-bound form and the inactive GDP-bound form under the regulation of dedicated guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). More than 80 human GEFs and 70 GAPs have been identified, most of which are expressed in the brain with a specific spatial and temporal expression pattern. However, the function of most GEFs and GAPs in the brain has not been elucidated. In this review, we highlight the novel neuronal function of the synaptic RhoGAP ARHGAP12 and the ID-associated RhoGEF TRIO and further propose 3 possible approaches of neurons utilizing Rho GTPase regulatory proteins to accurately modulate synaptic function.