PAK1 regulates inhibitory synaptic function via a novel mechanism mediated by endocannabinoids.

The Rho family small GTPases and their effectors, including PAKs, are extensively studied in the context of the actin cytoskeleton, excitatory synaptic function, spine morphology and memory formation. However, their roles in inhibitory synaptic function remain poorly understood. We have recently shown that PAK1 is a potent regulator of GABAergic synaptic transmission. Thus, disruption of PAK1 leads to significant impairments in inhibitory postsynaptic currents which are manifested as reduced GABA presynaptic releases. Interestingly, this effect of PAK1 is distinct from its previously known role in spines and excitatory synaptic transmission in that it is independent of postsynaptic actin, but requires retrograde messengers produced and released from the postsynaptic neurons to suppress presynaptic GABA releases. We have further identified eCBs as the retrograde messengers and shown that PAK1 regulates the eCB signaling via restricting the tissue level of AEA by promoting synaptic expression of COX-2, a key enzyme to oxidize AEA. These results have established a novel pathway whereby PAK1, and by extension Rho proteins, regulates cellular processes, synaptic function and behaviors and have important implications in understanding and treating various diseases linked to PAKs and Rho signaling.