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 (VGCC) function dictating their behavior during various forms of activity. We demonstrate that in vitro Munc13 interacts with voltage-VGCCs 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.
    Full-text · Article · Jul 2015 · eLife Sciences
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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.
    Full-text · Article · Feb 2015 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    • "Therefore, calcineurin activity might be important for the maintenance of spontaneous exocytosis at high levels when membrane cholesterol content is decreased. It is possible that calcineurin activation may increase theMarra et al. 2012), whereas genetic knockdown of calcineurin increased the size of the resting pool (Kim & Ryan, 2010). Another possibility is that calcineurin activity may be required for efficient endocytosis, leading to the formation of 'hot' vesicles with an increased ability to fuse (Rose et al. 2013). "
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    ABSTRACT: Using electrophysiological and optical techniques, we studied the mechanisms by which cholesterol depletion stimulates spontaneous transmitter release by exocytosis at the frog neuromuscular junction. We found that methyl-β-cyclodextrin (MCD, 10 mM)-mediated exhaustion of cholesterol resulted in the enhancement of reactive oxygen species (ROS) production which was prevented by the antioxidant (N-acetyl cysteine, NAC) and NADPH oxidase inhibitor (apocynin). An increase in ROS levels occurred both extra- and intracellularly, and it was associated with lipid peroxidation in synaptic regions. Cholesterol depletion provoked a rise in the intracellular Ca2+ concentration, which was diminished by NAC and TRPV channels blockers (ruthenium red and capsazepine). On the other hand, the MCD-induced rise in [Ca2+]i remained unaffected if Ca2+ release from endoplasmic stores was blocked by TMB8. The effects of cholesterol depletion on spontaneous release and exocytosis were significantly reduced by the antioxidant, intracellular Ca2+ chelation with BAPTA-AM, and blockers of TRPV channels. Bath application of the calcineurin antagonist, cyclosporine A, blocked MCD-induced enhancement of spontaneous release/exocytosis, whereas okadaic acid, an inhibitor of phosphatases PP1 and PP2A, had no effect. Thus, our findings indicate that enhancement of spontaneous exocytosis induced by cholesterol depletion may depend on ROS generation, leading to an influx of Ca2+ via TRPV channels and, subsequently, activation of calcineurin.This article is protected by copyright. All rights reserved
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