title: Control of Ca2+ Influx and Calmodulin Activation by SK-Channels in Dendritic Spines.
abstract: The key trigger for Hebbian synaptic plasticity is influx of Ca2+ into postsynaptic dendritic spines. The magnitude of [Ca2+] increase caused by NMDA-receptor (NMDAR) and voltage-gated Ca2+ -channel (VGCC) activation is thought to determine both the amplitude and direction of synaptic plasticity by differential activation of Ca2+ -sensitive enzymes such as calmodulin. Ca2+ influx is negatively regulated by Ca2+ -activated K+ channels (SK-channels) which are in turn inhibited by neuromodulators such as acetylcholine. However, the precise mechanisms by which SK-channels control the induction of synaptic plasticity remain unclear. Using a 3-dimensional model of Ca2+ and calmodulin dynamics within an idealised, but biophysically-plausible, dendritic spine, we show that SK-channels regulate calmodulin activation specifically during neuron-firing patterns associated with induction of spike timing-dependent plasticity. SK-channel activation and the subsequent reduction in Ca2+ influx through NMDARs and L-type VGCCs results in an order of magnitude decrease in calmodulin (CaM) activation, providing a mechanism for the effective gating of synaptic plasticity induction. This provides a common mechanism for the regulation of synaptic plasticity by neuromodulators.
authors.affiliation: Department of Engineering Mathematics, University of Bristol, Bristol, United Kingdom.|Bristol Centre for Complexity Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Thom
authors.initials: T
authors.lastname: Griffith
authors.affiliation: Department of Mathematics, College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter, United Kingdom.|EPSRC Centre for Predictive Modelling in Healthcare, University of Exeter, Exeter, United Kingdom.
authors.forename: Krasimira
authors.initials: K
authors.lastname: Tsaneva-Atanasova
authors.affiliation: Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom.
authors.forename: Jack R
authors.initials: JR
authors.lastname: Mellor
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling; D002147:Calmodulin / Q000378:metabolism*; D019295:Computational Biology; D049229:Dendritic Spines / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials; D021621:Imaging, Three-Dimensional; D017774:Long-Term Potentiation; D036881:Long-Term Synaptic Depression; D008959:Models, Neurological; D009473:Neuronal Plasticity; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*
chemical_list: D020746:Calcium Channels, L-Type; D002147:Calmodulin; D016194:Receptors, N-Methyl-D-Aspartate; D051640:Small-Conductance Calcium-Activated Potassium Channels