Deciphering the molecular mechanisms of cyclase-associated protein 1 (CAP1) in regulating dendritic spine morphology and structural plasticity

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Actin filaments (F-actin) determine the morphology of dendritic spines, the postsynaptic compartment of most excitatory synapses in the brain. Activity-induced spine morphological changes (termed structural plasticity) caused by F-actin assembly and disassembly supports synaptic plasticity and is relevant for brain functions like learning and memory. Hence, actin-binding proteins (ABP) that control F-actin dynamics moved into the focus as critical regulators of synapse physiology, brain function and behavior. Studies from us and others identified ABP of the ADF/cofilin family as key regulators of F-actin dynamics in spines. Moreover, these studies revealed that a tight regulation of cofilin1 activity in spines is mandatory for proper synapse function and that cofilin1 dysregulation caused cellular and behavioral deficits associated with human neuropsychiatric disorders. Our unpublished data identified cyclase-associated protein 1 (CAP1) as a novel actin regulator in spines that is relevant for spine morphology and structural plasticity. Moreover, they demonstrated functional interdependence of CAP1 and cofilin1 in regulating spine morphology. CAP1 contains several conserved protein domains that presumably allow interaction with a variety of proteins apart from actin and cofilin1. I therefore propose that CAP1 acts as a molecular hub in spines relevant for the activity of various interactors including cofilin1 and that upstream regulatory mechanisms act on CAP1 to control the machinery that governs F-actin dynamics in spines. The proposed project is designed to identify novel synaptic CAP1 interaction partners that are relevant for CAP1 function and its interaction with cofilin1 in spines. From our proposal we expect important novel insights into the mechanisms that control synaptic F-actin dynamics, spine morphology and structural plasticity.