Kim SH, Ryan TA.
CDK5 serves as a major control point in neurotransmitter release.
Neuron. 2010 Sep 9;67(5):797-809.
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In this paper, Kim and Ryan add compelling evidence to the growing literature that Cdk5 plays a critical role in synapse function. Using cultured hippocampal neurons tagged with vGlut1-pHluorin, they demonstrate that acute silencing of Cdk5 activity, through roscovitine or shRNA-mediated Cdk5 knockdown, results in increased pre-synaptic function. Based on a series of thorough measurements, they conclude that Cdk5 normally serves to repress neurotransmitter release by maintaining silent synapses and keeping the pool of recycling synaptic vesicles smaller, while preventing access to a larger resting pool. Furthermore, Cdk5 and calcineurin cooperate to maintain the recycling vesicle pool, suggesting that there is finely tuned regulation at the nerve terminal. Additional evidence comes from chronic silencing of neuronal activity using tetrodotoxin, which also downregulated Cdk5; intriguingly, this downregulation is due to a reduction in Cdk5 levels at the pre-synaptic terminal.
Cdk5 has previously been implicated in the phosphorylation of various pre-synaptic proteins involved in endocytosis, and this new finding underscores the importance of Cdk5 in the neurotransmitter release and exocytosis pathways. Moreover, these new findings are consistent with a previously described role of Cdk5 in maintaining homeostatic synaptic scaling (Seeburg et al., 2008). Because Cdk5 dysregulation is also implicated in neurodegenerative diseases such as Alzheimer disease (Patrick et al., 1999), in which there is synapse loss, understanding the physiological role of Cdk5 at the synapse and in learning and memory will shed new light on the molecular pathologies leading to cognitive impairment. This important work highlights a central role for Cdk5 in neurotransmitter release and opens the door for examining how Cdk5 maintains synaptic homeostasis in normal and neurodegenerative disease states.
Seeburg DP, Feliu-Mojer M, Gaiottino J, Pak DT, Sheng M.
Critical role of CDK5 and Polo-like kinase 2 in homeostatic synaptic plasticity during elevated activity.
Neuron. 2008 May 22;58(4):571-83.
Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH.
Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration.
Nature. 1999 Dec 9;402(6762):615-22.