CDK5 Serves as a Major Control Point in Neurotransmitter Release

Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
Neuron (Impact Factor: 15.05). 09/2010; 67(5):797-809. DOI: 10.1016/j.neuron.2010.08.003
Source: PubMed


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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Available from: Timothy A Ryan, Feb 27, 2014
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    • "Hippocampal CA3–CA1 regions were dissected from 1-to 3-day-old Sprague Dawley rats, dissociated, plated, and transfected as previously described (Kim and Ryan, 2010). All imaging experiments were performed as previously described with laser illumination and EM-CCD image collection (Hoppa et al., 2012) and carried out at 37˚C. "
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    ABSTRACT: Presynaptic calcium channel function is critical for converting electrical information into chemical communication but the molecules in the active zone that sculpt this function are poorly understood. We show that Munc13, an active-zone protein essential for exocytosis, also controls presynaptic voltage-gated calcium channel function dictating their behavior during various forms of activity. We demonstrate that in vitro Munc13 interacts with voltage-gated calcium channels via a pair of basic residues in Munc13's C2B domain. We show that elimination of this interaction by either removal of Munc13 or replacement of Munc13 with a Munc13 C2B mutant alters synaptic VGCC's response to and recovery from high-frequency action potential bursts and alters calcium influx from single action potential stimuli. These studies illustrate a novel form of synaptic modulation and show that Munc13 is poised to profoundly impact information transfer at nerve terminals by controlling both vesicle priming and the trigger for exocytosis.
    eLife Sciences 07/2015; 4. DOI:10.7554/eLife.07728 · 9.32 Impact Factor
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    • "Cdk5 has been shown to regulate synaptic vesicle pathways by phosphorylating the dephosphin proteins, such as dynamin I and synaptojanin, that, in turn, are dephosphorylated by the protein phosphatase calcineurin (Matsubara et al., 1996; Cousin et al., 2001; Lee et al., 2004). Interestingly , Kim and Ryan (2010) "
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    ABSTRACT: Perturbations in fast-spiking parvalbumin (PV) interneurons are hypothesized to be a major component of various neuropsychiatric disorders; however, the mechanisms regulating PV interneurons remain mostly unknown. Recently, cyclin-dependent kinase 5 (Cdk5) has been shown to function as a major regulator of synaptic plasticity. Here, we demonstrate that genetic ablation of Cdk5 in PV interneurons in mouse brain leads to an increase in GABAergic neurotransmission and impaired synaptic plasticity. PVCre;fCdk5 mice display a range of behavioral abnormalities, including decreased anxiety and memory impairment. Our results reveal a central role of Cdk5 expressed in PV interneurons in gating inhibitory neurotransmission and underscore the importance of such regulation during behavioral tasks. Our findings suggest that Cdk5 can be considered a promising therapeutic target in a variety of conditions attributed to inhibitory interneuronal dysfunction, such as epilepsy, anxiety disorders, and schizophrenia. Copyright © 2015 the authors 0270-6474/15/352372-12$15.00/0.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 02/2015; 35(6):2372-83. DOI:10.1523/JNEUROSCI.0969-14.2015 · 6.34 Impact Factor
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    • "Numerous studies have shown that synapsin I phosphorylation at serine 553 and 62/67 sites increases the probability of neurotransmitter release from synaptic vesicles [28], [29]. However, the potential relationship of p-Syn I to the aberrant neurotransmitter release associated with microwave-induced impairment of learning and memory has been poorly understood. "
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    ABSTRACT: Abnormal release of neurotransmitters after microwave exposure can cause learning and memory deficits. This study investigated the mechanism of this effect by exploring the potential role of phosphorylated synapsin I (p-Syn I). Wistar rats, rat hippocampal synaptosomes, and differentiated (neuronal) PC12 cells were exposed to microwave radiation for 5 min at a mean power density of 30 mW/cm2. Sham group rats, synaptosomes, and cells were otherwise identically treated and acted as controls for all of the following post-exposure analyses. Spatial learning and memory in rats was assessed using the Morris Water Maze (MWM) navigation task. The protein expression and presynaptic distribution of p-Syn I and neurotransmitter transporters were examined via western blotting and immunoelectron microscopy, respectively. Levels amino acid neurotransmitter release from rat hippocampal synaptosomes and PC12 cells were measured using high performance liquid chromatograph (HPLC) at 6 hours after exposure, with or without synapsin I silencing via shRNA transfection. In the rat experiments, there was a decrease in spatial memory performance after microwave exposure. The expression of p-Syn I (ser-553) was decreased at 3 days post-exposure and elevated at later time points. Vesicular GABA transporter (VGAT) was significantly elevated after exposure. The GABA release from synaptosomes was attenuated and p-Syn I (ser-553) and VGAT were both enriched in small clear synaptic vesicles, which abnormally assembled in the presynaptic terminal after exposure. In the PC12 cell experiments, the expression of p-Syn I (ser-553) and GABA release were both attenuated at 6 hours after exposure. Both microwave exposure and p-Syn I silencing reduced GABA release and maximal reduction was found for the combination of the two, indicating a synergetic effect. p-Syn I (ser-553) was found to play a key role in the impaired GABA release and cognitive dysfunction that was induced by microwave exposure.
    PLoS ONE 04/2014; 9(4):e95503. DOI:10.1371/journal.pone.0095503 · 3.23 Impact Factor
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