title: Calcium sensor regulation of the CaV2.1 Ca2+ channel contributes to short-term synaptic plasticity in hippocampal neurons.
abstract: Short-term synaptic plasticity is induced by calcium (Ca(2+)) accumulating in presynaptic nerve terminals during repetitive action potentials. Regulation of voltage-gated CaV2.1 Ca(2+) channels by Ca(2+) sensor proteins induces facilitation of Ca(2+) currents and synaptic facilitation in cultured neurons expressing exogenous CaV2.1 channels. However, it is unknown whether this mechanism contributes to facilitation in native synapses. We introduced the IM-AA mutation into the IQ-like motif (IM) of the Ca(2+) sensor binding site. This mutation does not alter voltage dependence or kinetics of CaV2.1 currents, or frequency or amplitude of spontaneous miniature excitatory postsynaptic currents (mEPSCs); however, synaptic facilitation is completely blocked in excitatory glutamatergic synapses in hippocampal autaptic cultures. In acutely prepared hippocampal slices, frequency and amplitude of mEPSCs and amplitudes of evoked EPSCs are unaltered. In contrast, short-term synaptic facilitation in response to paired stimuli is reduced by ∼ 50%. In the presence of EGTA-AM to prevent global increases in free Ca(2+), the IM-AA mutation completely blocks short-term synaptic facilitation, indicating that synaptic facilitation by brief, local increases in Ca(2+) is dependent upon regulation of CaV2.1 channels by Ca(2+) sensor proteins. In response to trains of action potentials, synaptic facilitation is reduced in IM-AA synapses in initial stimuli, consistent with results of paired-pulse experiments; however, synaptic depression is also delayed, resulting in sustained increases in amplitudes of later EPSCs during trains of 10 stimuli at 10-20 Hz. Evidently, regulation of CaV2.1 channels by CaS proteins is required for normal short-term plasticity and normal encoding of information in native hippocampal synapses.
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195-7280;
authors.forename: Evanthia
authors.initials: E
authors.lastname: Nanou
authors.affiliation: Department of Physiology & Biophysics, University of Washington, Seattle, WA 98195-7290.
authors.forename: Jane M
authors.initials: JM
authors.lastname: Sullivan
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195-7280;
authors.forename: Todd
authors.initials: T
authors.lastname: Scheuer
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195-7280; wcatt@uw.edu.
authors.forename: William A
authors.initials: WA
authors.lastname: Catterall
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020864:Calcium Channels, N-Type / Q000502:physiology*; D002478:Cells, Cultured; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D006624:Hippocampus / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000502:physiology*
chemical_list: D002118:Calcium; D020864:Calcium Channels, N-Type
keywords: calcium channel; calcium sensor proteins; calmodulin; hippocampus; synaptic facilitation