Physiological functions of Cdk5 in the nervous system
Cdk5 was discovered about 15 years ago based on homology to Cdc2. It is now clear that Cdk5 does not regulate the cell cycle, but rather is active in post-mitotic neurons. Mice with deficiencies in Cdk5 activity have staggering developmental defects, including an inverted neocortex and massive disruptions in the hippocampus and cerebellum. Logically, much research has focused on molecular and cellular mechanisms determining how Cdk5 orchestrates neuronal positioning during development. This seminal work has provided a fundamental understanding of how neuronal migration shapes the developing brain. However, while activity remains high throughout adulthood, insight into Cdk5 functions in the more mature nervous system have remained limited. Compelling evidence has recently demonstrated that a Cdk5 gain-of-function mouse model has an increased number of synapses and enhanced learning ability.
Here I demonstrate that two synaptic proteins, CASK and N-type calcium channels are Cdk5 substrates. CASK is a scaffolding molecule that is recruited to newly forming synapses where it interacts with essential presynaptic machinery including the synaptic vesicle release apparatus and voltage-gated calcium channels. Cdk5-dependent phosphorylation regulates CASK distribution to membrane compartments, is required for CASK recruitment to developing synapses and promotes interactions between CASK and the presynaptic machinery. In the absence of CASK localization to synapses, calcium influx through voltage-gated channels is impaired. Therefore, CASK represents a potential mechanism of how Cdk5 regulates presynaptic molecules to promote synaptogenesis. Interestingly, Cdk5 also phosphorylates the presynaptically enriched N-type calcium channel, which results in a profound increase in channel activity. Therefore, Cdk5 enhances the functions of multiple players at the emerging presynaptic terminal.
Here I also characterize an inducible Cdk5 loss-of-function mouse that expresses a dominant-negative Cdk5 (dnk5) transgene. A mosaic expression pattern in CA1 and the Dentate Gyrus results in roughly a 30-40% decrease of Cdk5 activity in the hippocampus and decreased phosphorylation of several Cdk5 substrates. Furthermore, impairments in contextual fear conditioning and the Morris water maze underscore the importance of Cdk5 for learning. Interestingly, dnk5 decreases the density of dendritic spines and alters dendritic branching, suggesting that a decreased number of synapses partially accounts for the behavioral phenotype.