SK2 channel plasticity contributes to LTP at Schaffer collateral–CA1 synapses

Abstract

Long-term potentiation (LTP) of synaptic strength at Schaffer collateral synapses has largely been attributed to changes in the number and biophysical properties of AMPA receptors (AMPARs). Small-conductance Ca 2+ -activated K + channels (SK2 channels) are functionally coupled with NMDA receptors (NMDARs) in CA1 spines such that their activity modulates the shape of excitatory postsynaptic potentials (EPSPs) and increases the threshold for induction of LTP. Here we show that LTP induction in mouse hippocampus abolishes SK2 channel activity in the potentiated synapses. This effect is due to SK2 channel internalization from the postsynaptic density (PSD) into the spine. Blocking PKA or cell dialysis with a peptide representing the C-terminal domain of SK2 that contains three known PKA phosphorylation sites blocks the internalization of SK2 channels after LTP induction. Thus the increase in AMPARs and the decrease in SK2 channels combine to produce the increased EPSP underlying LTP.Activity-dependent changes in synaptic strength are widely believed to underlie the cellular mechanisms of learning and memory. This view has gained significant support from recent studies showing that learning induces long-lasting changes in synaptic strength 1-3 . At Schaffer collateral-to-CA1 synapses in the hippocampus, stimulation protocols that coordinate presynaptic and postsynaptic activity to induce LTP affect the postsynaptic cell through a process that is dependent upon NMDAR activity and Ca 2+ influx into the stimulated dendritic spine 4-6 . LTP inducing protocols act through PKA and calcium/calmodulin-dependent kinase II (CaMKII) to alter the biophysical properties 7-9 and increase the number of AMPARs in the PSD 10-14 .SK2 channels are activated solely by intracellular Ca 2+ ions, with submicromolar Ca 2+ affinity 15 , and are selectively blocked by the peptide toxin apamin. SK2 channels are expressed throughout the dendritic arbor of CA1 neurons and in dendritic spines 16,17 . Whole-cell current-clamp recordings and Ca 2+ imaging revealed that spine SK2 channels are activated by synaptically driven Ca 2+ influx 16 . The repolarizing effect of SK2 channel activity opposes the depolarizing effect of AMPAR activity, reducing the EPSP, favoring Mg 2+ reblocking of NIH Public Access Author ManuscriptNat Neurosci. Author manuscript; available in PMC 2009 January 5. Published in final edited form as:Nat Neurosci. 2008 February ; 11(2): 170-177. doi:10.1038/nn2041. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptNMDARs and reducing the Ca 2+ transient 16 . SK2 channels are therefore ideally suited to modulate the induction of synaptic plasticity. Indeed, field recordings in area CA1 showed that blocking SK2 channels facilitates the induction of synaptic plasticity. In addition, administration of apamin to mice facilitates hippocampal-dependent memory encoding 18 . In contrast, overexpression of SK2 channels in transgenic mice impairs the induction of synaptic plasticity and severely impairs hippoc...

Optogenetic photochemical control of designer K+channels in mammalian neurons

“…There are four members of the SK channel family, and three of them, SK1, SK2, and SK3, are expressed in central nervous system neurons (Stocker et al 2000). In CA1 hippocampal neurons, SK2 channels modulate EPSPs and contribute to long-term potentiation (LTP) of synaptic transmission (Lin et al 2008;NgoAnh et al 2005).…”

Learning-related postburst afterhyperpolarization reduction in CA1 pyramidal neurons is mediated by protein kinase A

“…PKA has also been shown to effectively reduce the AHP in hippocampal pyramidal neurons (23,45). Recently, Lin et al (46) demonstrated that activated PKA induces internalization of the apamin-sensitive AHP channels, SK2, in the dendritic spines of hippocampal neurons. In addition, compounds that reduce the AHP facilitate LTP induction (15,(47)(48)(49).…”

“…Recently, Hoffman and colleagues demonstrated that PKA activation led to Kv4.2 channels being removed from the surface of the cell membrane (62), similar to the SK2 apamin-sensitive AHP channels (46). The internalization of the Kv4.2 via PKA activity results in a reduced A-type potassium current (62).…”

NR2A at CA1 Synapses Is Obligatory for the Susceptibility of Hippocampal Plasticity to Sleep Loss

“…The length of the postsynaptic density was measured on ultrathin sections and the number of immunoparticles per postsynaptic density was counted. This procedure was shown previously to provide reliable estimates of NMDAR subunit density (Lin et al, 2008). Finally, the density of NR2A or NR2B along the postsynaptic densities of dendritic spines of pyramidal cells, measured as number of immunoparticles per micrometer, was calculated in control conditions, after SD and in NR2A KO mice.…”