Pharmacological inactivation of the small GTPase Rac1 impairs long-term plasticity in the mouse hippocampus

Neuronal development involves several discrete morphological steps requiring migration of newborn neurons to characteristic locations, extension of axons and dendrites into proper target regions, and formation of synapses with appropriate partners. Small GTPases such as Rac1, are believed to be critical regulators of these processes. We have previously reported that Rac1 is highly expressed in mouse hippocampus, where NMDA receptor activation causes Rac1 to translocate to the membrane in a manner similar to that observed in other 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 plays also an active and critical role in these types of long-term synaptic plasticity. We found that activation of Rac1 is associated with long-term plasticity, both LTP and LTD. 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. The results of these experiments provide essential knowledge regarding the signaling mechanisms that underlie synaptic plasticity, as well as learning and memory processes, which in turn offers insights into the basis of diseases involving memory impairment, such as Fragile X syndrome, Alzheimer’s disease, William’s syndrome, Angelman syndrome (AS), and schizophrenia. ► NSC23766 and EHT1864 are effective inhibitors of Rac1 in brain tissue. ► Effects of NSC23766 and EHT1864 in brain are reversible. ► Inactivation of Rac1 impairs NMDA receptor-dependent long-term potentiation. ► Inactivation of Rac1 impairs also long-term depression. ► Rac1 is important for the induction phase of long-term plasticity.