Distinct Roles of the Rho-GTPase Associated Kinases PAK and ROCK in the Regulation of Dendritic Spines and Synaptic Plasticity

Dendritic spines are highly specialized neuronal structures that are the major postsynaptic sites for excitatory input. These actin-rich expansions are highly versatile in adapting their morphology and density towards the support of synaptic transmission and plasticity. Among the chief factors known to be crucial in the modulation of the actin cytoskele- ton, the Rho-GTPases and their associated signaling effectors are particularly important. This signaling system is involved in numerous regulatory processes, including cell morphology, structural dynamics and cell motility. Accordingly, the dis- ruption of Rho-related signaling has a profound effect on the integrity of neurons, resulting in abnormalities with neurite outgrowth, dendritic arborization, spine properties and plasticity. These perturbations can dramatically alter normal synap- tic function, including hippocampal long-term potentiation (LTP), resulting in cognitive defects. Additionally, Rho- GTPase-associated signaling disorders have also been implicated in numerous forms of mental retardation. Therefore, the elucidation of the underlying mechanisms involved in this pathway and their critical association with dendritic spines re- mains a major focus of research concerning the cellular basis of cognitive function. Here we will discuss our recent data obtained utilizing knockout animals deficient in the expression of PAKs (p21-activated kinases) and ROCKs (Rho- kinases), predominant protein kinases known to be directly activated by the Rho-GTPases. A downstream target for both PAKs and ROCKs, LIMKs (Lin-11, Isl-1, and Mec-3 kinase), will also be discussed. While it is evident that these kinase families all serve towards spine and synaptic regulation, their individual roles in the achievement of this goal may be quite different.