A Critical Role for the small GTPase Rac1 in long-term plasticity

Synaptic plasticity involves morphological changes at neuronal connections giving rise to phenomena such as Long Term Potentiation (LTP) and Long Term Depression (LTD). These changes require modifications of the actin cytoskeleton which are regulated by small GTPases such as Rac1. We have previously reported that Rac1 is highly expressed in mouse hippocampus, a brain region important in memory formation, where NMDA receptor activation causes Rac1 to translocate to the membrane in a manner similar to that observed in non-neuronal cells. Additionally Rac1 has been seen to play a role in activation of signal transduction pathways associated with hippocampal learning and memory. Because of the established role of LTP and LTD in learning and memory processes, in this study we investigate whether Rac1 also plays an active and critical role in these forms of long-term plasticity. Using electrophysiological techniques to induce LTP and LTD we found activation of Rac1 to be associated with both types of plasticity. Rac1 appears to have a transient role during the induction of NMDA receptor-dependent LTP, but does not have an effect on LTP maintenance and expression. Similar results were found for NMDA receptor-dependent induction of LTD, while mGluR-dependent LTD was shown to be significantly altered but not abolished. Characteristics of neurological disorders such as Fragile X syndrome, Alzheimer’s disease, William’s syndrome, Angelman syndrome (AS), and schizophrenia involve memory impairments as well as abnormal synaptic structures. Thus the results of these experiments provide insight into perturbed mechanisms of synaptic plasticity and potential targets of therapeutic intervention.