Deconstructing signal transduction pathways that regulate the actin cytoskeleton in dendritic spines.

Dendritic spines are the sites of most excitatory synapses in the central nervous system. Recent studies have shown that spines function independently of each other, and they are currently the smallest known processing units in the brain. Spines exist in an array of morphologies, and spine structure helps dictate synaptic function. Dendritic spines are rich in actin, and actin rearrangements are critical regulators of spine morphology and density. In this review, we discuss the importance of actin in regulating dendritic spine morphogenesis, and discuss the upstream signal transduction pathways that either foster or inhibit actin polymerization. The understanding of actin regulatory pathways is best conceptualized as a hierarchical network in which molecules function in discrete levels defined by their molecular distance to actin. To this end, we focus on several classes of molecules, including guanine nucleotide exchange factors, small GTPases, small GTPase effectors, and actin binding proteins. We discuss how individual proteins in these molecular classes impact spine morphogenesis, and reveal the biochemical interactions in these networks that are responsible for shaping actin polymerization. Finally, we discuss the importance of these actin regulatory pathways in neuropsychiatric disorders.