Long term potentiation of synaptic strength (LTP) at Schaffer collateral synapses has largely been attributed to changes in the number and biophysical properties of a-amino-3-hydroxy-5-methylisoxazole-4- propionic acid receptors (AMPAr). Small conductance Ca2+ activated K+ channels (SK2 channels) are functionally coupled with N-methyl-D-aspartate receptors (NMDAr) in CA1 spines such that their activity modulates the shape of excitatory postsynaptic potentials (EPSPs) and increases the threshold for induction of LTP. Blocking SK2 channels facilitates CA1 neuron plasticity in hippocampus and promotes animal acquisition of hippocampal dependent learning tasks. Moreover, overexpressing SK2 channels in CA1 neurons in transgenic mice impairs the induction of synaptic plasticity and hippocampal-dependent memory encoding. Therefore, SK2 channels modulate the induction of synaptic plasticity. My preliminary data show that SK2 channels additionally contribute to LTP. The induction of LTP at Schaffer collateral synapses abolishes SK2 channel activity in the potentiated synapses. This effect is due to SK2 channel intemalization from the postsynaptic density (PSD) into the spine. Blocking PKA or cell dialyzed with a peptide representing the C-terminal domain of SK2 that contains three known PKA phosphorylation sites blocks the intemalization of SK2 channels following LTP induction. Thus the increase in AMPAr and the decrease in SK2 channel combine to produce the increased EPSP underlying LTP. SK2 channel plasticity contributes ~14% to LTP. While this is a significant contribution, the increased AMPAr contribution to the EPSP accounts for the majority of the increased excitability. However, the functional consequence of SK2 channel endocytosis upon the induction of LTP may be more significant for the effect on subsequent synaptic activity. SK2 channels in the spines of CA1 neurons provide a negative feedback that attenuates the Ca2+ influx through NMDAr. The lost repolarizing effect mediated by the SK2 channels will profoundly increase the amount of Ca2+ entering through NMDAr (at least 40%) upon subsequent synaptic activity. This will effectively facilitate the induction of plasticity. Therefore, it is important to determine the fates of the SK2 channels once they are removed from potentiated spines and the PKA signaling mechanisms involved. This proposal is targeted to study the basic mechanisms of synaptic plasticity and memory formation, and will contribute to our fundamental knowledge in plasticity and learning process.
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