CDK5 is an important kinase in nervous system function, controlling neural development and postsynaptic signal integration. Here we show that CDK5 plays a major role in controlling neurotransmitter release. Inhibition of CDK5 activity, by either acute or genetic means, leads to profound potentiation of presynaptic function, including unmasking of previously "silent" synapses. Removal of CDK5 activity additionally unlocks access to the resting synaptic vesicle pool, which normally remains recalcitrant to exocytosis and recycling even following prolonged action potential stimuli. Presynaptic CDK5 levels are additionally severely depleted by chronic neuronal silencing, a treatment that is functionally similar to CDK5 knockdown with regard to presynaptic potentiation. Thus CDK5 appears to be an integral element in presynaptic homeostatic scaling, and the resting vesicle pool appears to provide a potent functional presynaptic homeostatic control parameter. These studies thus pinpoint CDK5 as a major control point for modulation of neurotransmitter release in mammalian neurons.
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