Elucidating how cyclin-dependent kinase 5 (Cdk5) regulates synapse function in neuron

Abstract

Our brain function depends on communication between neurons through synaptic transmission. Most excitatory synapses are located on specialized protrusions on the dendrites called dendritic spines, which have heterogeneous morphologies and are highly dynamic. The stability and morphology of dendritic spines can be regulated by synaptic activity and specific growth factors such as the neurotrophin BDNF. This activity-dependent spine morphogenesis is a crucial mechanism by which experience modulates the efficacy of synaptic transmission, and is fundamental to brain development and function such as memory formation. Indeed, altered spine density and morphology is associated with neurodevelopmental disorders including intellectual disability and autism. Delineating the molecular mechanisms that underlie dendritic spine development and remodeling might therefore provide important insights into the molecular basis of various mental disorders. Spine growth and remodeling requires changes in actin cytoskeleton, gene transcription and protein synthesis that involve multiple signaling cascades regulated through protein phosphorylation. Emerging evidence suggests that the serine/threonine kinase Cdk5 is critically involved in regulating synapse function and synaptic plasticity, but the underlying mechanisms remain elusive. Here I will describe the function of Cdk5 in promoting dendritic spine morphogenesis via phosphorylation of the BDNF receptor TrkB and the signaling protein S6 kinase (p70S6K1). Through identification of the major phosphorylation sites and generation of phospho-deficient mutants, the importance of Cdk5-mediated phosphorylation of TrkB and p70S6K1 in activity-dependent spine plasticity and maturation will be discussed.