Control of Ca2+ Influx and Calmodulin Activation by SK-Channels in Dendritic Spines.

Kim T Blackwell,Thom Griffith,Jack R Mellor,Krasimira Tsaneva-Atanasova

doi:10.1371/journal.pcbi.1004949

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.

Highlights

Associative learning is underpinned by Hebbian synaptic plasticity at glutamatergic synapses.Spike timing-dependent plasticity (STDP) is the classical manifestation of Hebbian plasticity where temporally correlated pre- and post-synaptic activity induces NMDA receptor (NMDAR)- and Ca2+ -dependent changes in synaptic strength [1,2,3]
Hebbian or associative plasticity is triggered by postsynaptic Ca2+ influx which activates calmodulin and calmodulin-activated kinase II (CaMKII)
Using 3-dimensional modeling of Ca2+ and calmodulin dynamics within dendritic spines we show that the non-linear relationship between Ca2+ influx and calmodulin activation endows SK-channels with the ability to “gate” calmodulin activation and the induction of Hebbian synaptic plasticity

Summary

Introduction

Associative learning is underpinned by Hebbian synaptic plasticity at glutamatergic synapses.Spike timing-dependent plasticity (STDP) is the classical manifestation of Hebbian plasticity where temporally correlated pre- and post-synaptic activity induces NMDA receptor (NMDAR)- and Ca2+ -dependent changes in synaptic strength [1,2,3]. The requirement for Ca2+ influx through voltage-gated Ca2+ channels (VGCCs) and temporally precise postsynaptic spiking [9,10,11] highlights the importance of spatiotemporal patterning of [Ca2+] within the postsynaptic spine for induction of STDP, the mechanisms for this remain obscure. The C-terminal lobe is high affinity with slow binding kinetics whilst the N-terminal lobe is low affinity with fast binding kinetics [14] This ensures that CaM activation by Ca2+ within spines will depend on the spatiotemporal pattern of [Ca2+] transients. It is predicted that SK-channels regulate spine Ca2+ dynamics which at the nanodomain-level control CaM activity and the induction of synaptic plasticity

Methods

Findings

Discussion

Conclusion