Abstract
Dendritic spine stabilization depends on afferent synaptic input and requires changes in actin cytoskeleton dynamics and protein synthesis. However, the underlying molecular mechanism remains unclear. Here we report the identification of ‘calmodulin kinase-like vesicle-associated' (CaMKv), a pseudokinase of the CaMK family with unknown function, as a synaptic protein crucial for dendritic spine maintenance. CaMKv mRNA localizes at dendrites, and its protein synthesis is regulated by neuronal activity. CaMKv function is inhibited upon phosphorylation by cyclin-dependent kinase 5 (Cdk5) at Thr345. Furthermore, CaMKv knockdown in mouse hippocampal CA1 pyramidal neurons impairs synaptic transmission and plasticity in vivo, resulting in hyperactivity and spatial memory impairment. These findings collectively indicate that the precise regulation of CaMKv through activity-dependent synthesis and post-translational phosphorylation is critical for dendritic spine maintenance, revealing an unusual signalling pathway in the regulation of synaptic transmission and brain function that involves a pseudokinase.
Highlights
Dendritic spine stabilization depends on afferent synaptic input and requires changes in actin cytoskeleton dynamics and protein synthesis
calmodulin kinase-like vesicle-associated’ (CaMKv) knockdown in mouse hippocampal CA1 pyramidal neurons impairs synaptic transmission and plasticity in vivo, resulting in hyperactivity and spatial memory impairment. These findings collectively indicate that the precise regulation of CaMKv through activity-dependent synthesis and post-translational phosphorylation is critical for dendritic spine maintenance, revealing an unusual signalling pathway in the regulation of synaptic transmission and brain function that involves a pseudokinase
CaMKv knockdown in the hippocampal CA1 neurons of mice enhances locomotor activity and impairs spatial memory performance. These results indicate that CaMKv serves as convergence point for the transduction of Ca2 þ signals to the neuronal cytoskeleton via RhoA; CaMKv interacts with Cdk[5] to regulate spine dynamics and contributes to normal synaptic transmission underlying brain function
Summary
Dendritic spine stabilization depends on afferent synaptic input and requires changes in actin cytoskeleton dynamics and protein synthesis. CaMKv knockdown in mouse hippocampal CA1 pyramidal neurons impairs synaptic transmission and plasticity in vivo, resulting in hyperactivity and spatial memory impairment These findings collectively indicate that the precise regulation of CaMKv through activity-dependent synthesis and post-translational phosphorylation is critical for dendritic spine maintenance, revealing an unusual signalling pathway in the regulation of synaptic transmission and brain function that involves a pseudokinase. It is critical to explicate the Ca2 þ -dependent signalling protein(s) that regulate Lfc and RhoA activity downstream of glutamate receptors to better understand activity-dependent spine maintenance. To understand how CaMK and Cdk[5] signalling interact to regulate synaptic function, we used mass spectrometry to generate a library of synaptic Cdk[5] substrates (unpublished observations) This exploratory study identified the protein CaMKv as a potential Cdk[5] substrate
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