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

Abstract

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...

Presynaptic Calcium Channels

“…Furthermore, the impairments in short-term and long-term plasticity due to Ca V 2.1 channel mutation at the IQ-like motif 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 CaM and nCaS is required for not only presynaptic facilitation but also induction of postsynaptic long-term potentiation, and spatial learning and memory [136].…”

The Role of CaV2.1 Channel Facilitation in Synaptic Facilitation

“…Although the reason for the reduced Ca V 2.1 channel density in some cell types in Ca IM-AA mice is not known, even a small decrement in calcium channel density can strongly reduce the initial synaptic strength, which in turn increases synaptic facilitation. These results raise the possibility that changes in Ca V 2.1 channel density in some types of neurons could contribute to behavioral phenotypes that have been observed in Ca IM-AA mice (Nanou et al, 2016b, 2016c). We note however that a reduction in Ca V 2.1 current density is only one factor that may influence the balance of synaptic depression and facilitation in Ca IM-AA animals.…”

Neurotransmitter Release Site Replenishment and Presynaptic Plasticity

“…Our electrophysiological study, following changes in EPSP after an AP, showed that release-ready SVs are controlled by the millisecond Ca 2+ dynamics [ 86 ] that activate multiple protein cascades via Ca 2+ -sensor molecules, including AZ proteins complex, motor proteins, and endocytic proteins [ 56 , 64 , 85 ] ( Figure 7 ). Furthermore, the millisecond Ca 2+ dynamics also control presynaptic Ca 2+ channels activity, by Ca 2+ bound CaM and neuron-specific Ca 2+ -binding proteins [ 121 , 141 , 148 , 151 ], to modulate Ca 2+ elevation with incoming APs. These multiple protein cascades activated by a single AP should be activated during and after bursts of APs, resulting in presynaptic short-term plasticity.…”