Understanding the molecular mechanism of activity-dependent structural plasticity in neuron

Abstract

Understanding the molecular mechanism of activity-dependent structural plasticity in neuron Precise regulation of dendritic arborization and dendritic spines by neuronal activity is critical to the proper functioning of nervous system. Two major signaling pathways are involved in transducing neuronal activity to long-lasting morphological changes of neurons: regulation of gene transcription in the nucleus, and rearrangement of cytoskeleton in dendritic spines. The proline-directed serine/threonine kinase Cdk5 is a multi-faceted signaling protein involved in diverse processes of neuronal development, but little is known if Cdk5 regulates activity-dependent dendritic arborization and spine morphogenesis. My study has demonstrated a crucial role of Cdk5 in activity-induced dendritic growth of young neurons through the regulation of gene transcription. Notably, nuclear Cdk5 was enriched by the visual stimulation and neuronal depolarization. Through genome-wide transcriptome analysis, I have identified bdnf as the target gene regulated by Cdk5, which might involve a MeCP2-dependent mechanism. These findings suggest that the nuclear import of Cdk5 is crucial for activity-dependent dendritic growth by regulating gene transcription in the nucleus. My study has further identified CaMKv, a pseudo-kinase of the calcium/calmodulin-dependent protein kinase family with unknown function, as a novel substrate of Cdk5. CaMKv promoted activity-dependent maintenance of dendritic spines in mature neurons through the inhibition of RhoA, a well-characterized Rho-GTPase that regulates neuronal cytoskeleton. On the other hand, the function of CaMKv was inhibited upon phosphorylation by Cdk5 at Thr-345. Knockdown of CaMKv in the hippocampal CA1 pyramidal neurons in vivo resulted in impaired synaptic transmission, hyperactivity and deficient spatial memory. These findings therefore reveal an unusual Cdk5-dependent regulatory mechanism of synapse function that involves a pseudokinase.

Date of Award	2015
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology