Fine-tuning synaptic plasticity by modulation of Ca V 2.1 channels with Ca 2+ sensor proteins

Jin

Whitehead

et al. 2016

Self Cite

Facilitation and inactivation of P/Q-type calcium (Ca 2+ ) currents through the regulation of voltage-gated Ca 2+ (Ca V ) 2.1 channels by Ca 2+ sensor (CaS) proteins contributes to the facilitation and rapid depression of synaptic transmission in cultured neurons that transiently express Ca V 2.1 channels. To examine the modulation of endogenous Ca V 2.1 channels by CaS proteins in native synapses, we introduced a mutation (IM-AA) into the CaS proteinbinding site in the C-terminal domain of Ca V 2.1 channels in mice, and tested synaptic facilitation and depression in neuromuscular junction synapses that use exclusively Ca V 2.1 channels for Ca 2+ entry that triggers synaptic transmission. Even though basal synaptic transmission was unaltered in the neuromuscular synapses in IM-AA mice, we found reduced short-term facilitation in response to paired stimuli at short interstimulus intervals in IM-AA synapses. In response to trains of action potentials, we found increased facilitation at lower frequencies (10-30 Hz) in IM-AA synapses accompanied by slowed synaptic depression, whereas synaptic facilitation was reduced at high stimulus frequencies (50-100 Hz) that would induce strong muscle contraction. As a consequence of altered regulation of Ca V 2.1 channels, the hindlimb tibialis anterior muscle in IM-AA mice exhibited reduced peak force in response to 50 Hz stimulation and increased muscle fatigue. The IM-AA mice also had impaired motor control, exercise capacity, and grip strength. Taken together, our results indicate that regulation of Ca V 2.1 channels by CaS proteins is essential for normal synaptic plasticity at the neuromuscular junction and for muscle strength, endurance, and motor coordination in mice in vivo.calcium channels | synaptic facilitation | calcium sensor proteins | calmodulin | synaptic plasticity C lassic work on the frog neuromuscular junction (NMJ) first described facilitation and depression of synaptic transmission during trains of action potentials (1). These forms of short-term plasticity are widespread among different types of synapses, and they transmit information encoded in the frequency and pattern of action potential generation to postsynaptic cells (2). Calcium (Ca 2+ )-dependent synaptic transmission is mediated by multiple types of voltage-gated Ca 2+ (Ca V ) channels. Mature mammalian NMJ synapses use exclusively Ca V 2.1 channels to initiate synaptic transmission (3), in contrast to central nervous system synapses that use combinations of Ca V 2.1, Ca V 2.2, and Ca V 2.3 channels (4-6). Disruption of Ca V 2.1 channels by elimination of their poreforming α1 subunit greatly reduces facilitation at the calyx of Held synapse (7,8) and the NMJ (9) in mice, suggesting a key role for Ca V 2.1 channels in short-term synaptic plasticity.Ca V 2.1 channels in transfected nonneuronal cells are regulated in a biphasic manner by calmodulin and other related Ca , and then interact with the CBD to induce Ca 2+ -dependent inactivation in response to longer, more global increases in Ca 2+...

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Altered short-term synaptic plasticity and reduced muscle strength in mice with impaired regulation of presynaptic Ca _V 2.1 Ca ²⁺ channels

Jin

Whitehead

et al. 2016

Self Cite

“…Ca 2+ -dependent facilitation and inactivation of P/Q-type Ca 2+ currents correlate with facilitation and rapid depression of synaptic transmission at the Calyx of Held (15)(16)(17)(18). Elimination of Ca V 2.1 channels by gene deletion prevents facilitation of synaptic transmission at the Calyx of Held (19,20 -dependent facilitation and inactivation of channel activity (22)(23)(24)(25)(26). Expression of these different CaS proteins with Ca V 2.1 channels in cultured sympathetic ganglion neurons results in corresponding bidirectional changes in facilitation and depression of the postsynaptic response (25,26).…”

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confidence: 99%

“…Elimination of Ca V 2.1 channels by gene deletion prevents facilitation of synaptic transmission at the Calyx of Held (19,20 -dependent facilitation and inactivation of channel activity (22)(23)(24)(25)(26). Expression of these different CaS proteins with Ca V 2.1 channels in cultured sympathetic ganglion neurons results in corresponding bidirectional changes in facilitation and depression of the postsynaptic response (25,26). Therefore, binding of CaS proteins to Ca V 2.1 channels at specific synapses can change the balance of CaS-dependent facilitation and inactivation of Ca V 2.1 channels, and determine the outcome of synaptic plasticity (27).…”

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confidence: 99%

Calcium sensor regulation of the Ca _V 2.1 Ca ²⁺ channel contributes to short-term synaptic plasticity in hippocampal neurons

Sullivan

Scheuer

et al. 2016

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Short-term synaptic plasticity is induced by calcium (Ca 2+ ) accumulating in presynaptic nerve terminals during repetitive action potentials. Regulation of voltage-gated Ca V 2.1 Ca 2+ channels by Ca 2+ sensor proteins induces facilitation of Ca 2+ currents and synaptic facilitation in cultured neurons expressing exogenous Ca V 2.1 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 Ca V 2.1 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 Ca V 2.1 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 Ca V 2.1 channels by CaS proteins is required for normal short-term plasticity and normal encoding of information in native hippocampal synapses.calcium channel | calcium sensor proteins | synaptic facilitation | calmodulin | hippocampus

“…Short-term and long-term modifications in synaptic strength are regulated by the frequency and pattern of presynaptic spiking (2-5). Regulation of voltage-gated Ca 2+ channel type 2.1 (Ca V 2.1) by calmodulin (CaM) and related Ca 2+ sensor (CaS) proteins causes Ca 2+ -dependent facilitation and inactivation of P/Qtype Ca 2+ currents (6-12) that results in short-term facilitation and rapid depression of synaptic transmission (9,(12)(13)(14). Deletion of the gene encoding Ca V 2.1 channels (15) or mutation of their CaS protein binding domain (12-14) impairs short-term synaptic plasticity.…”

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confidence: 99%

Calcium sensor regulation of the Ca _V 2.1 Ca ²⁺ channel contributes to long-term potentiation and spatial learning

Scheuer

Catterall

2016

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Many forms of short-term synaptic plasticity rely on regulation of presynaptic voltage-gated Ca 2+ type 2.1 (Ca V 2.1) channels. However, the contribution of regulation of Ca V 2.1 channels to other forms of neuroplasticity and to learning and memory are not known. Here we have studied mice with a mutation (IM-AA) that disrupts regulation of Ca V 2.1 channels by calmodulin and related calcium sensor proteins. Surprisingly, we find that long-term potentiation (LTP) of synaptic transmission at the Schaffer collateral-CA1 synapse in the hippocampus is substantially weakened, even though this form of synaptic plasticity is thought to be primarily generated postsynaptically. LTP in response to θ-burst stimulation and to 100-Hz tetanic stimulation is much reduced. However, a normal level of LTP can be generated by repetitive 100-Hz stimulation or by depolarization of the postsynaptic cell to prevent block of NMDA-specific glutamate receptors by Mg 2+ . The ratio of postsynaptic responses of NMDA-specific glutamate receptors to those of AMPA-specific glutamate receptors is decreased, but the postsynaptic current from activation of NMDA-specific glutamate receptors is progressively increased during trains of stimuli and exceeds WT by the end of 1-s trains. Strikingly, these impairments in long-term synaptic plasticity and the previously documented impairments in short-term synaptic plasticity in IM-AA mice are associated with pronounced deficits in spatial learning and memory in context-dependent fear conditioning and in the Barnes circular maze. Thus, regulation of Ca V 2.1 channels by calcium sensor proteins is required for normal short-term synaptic plasticity, LTP, and spatial learning and memory in mice.calcium channel | calmodulin | synaptic plasticity | calcium sensor proteins | hippocampus A ctivity-dependent modification of synaptic strength in synapses in the central nervous system is important for hippocampaldependent information processing and for spatial learning and memory (1). Short-term and long-term modifications in synaptic strength are regulated by the frequency and pattern of presynaptic spiking (2-5). Regulation of voltage-gated Ca 2+ channel type 2.1 (Ca V 2.1) by calmodulin (CaM) and related Ca 2+ sensor (CaS) proteins causes Ca 2+ -dependent facilitation and inactivation of P/Qtype Ca 2+ currents (6-12) that results in short-term facilitation and rapid depression of synaptic transmission (9,(12)(13)(14). Deletion of the gene encoding Ca V 2.1 channels (15) or mutation of their CaS protein binding domain (12-14) impairs short-term synaptic plasticity. Although regulation of Ca V 2.1 channels contributes to short-term synaptic plasticity in multiple types of synapses, the functional role of this form of synaptic regulation in learning and memory is unknown.Long-term potentiation (LTP) of synaptic transmission in the hippocampus is thought to be important for spatial learning and memory (16). High-frequency stimuli induce LTP, which depends on postsynaptic Ca 2+ entry via NMDA-specific glutamate rec...