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• W2917681567 abstract "•CaV2.1 facilitation did not contribute to synaptic facilitation with physiological stimuli•CaV2.1 facilitation is small for action potentials and 1.5 mM external Ca at 37°C•The magnitude of CaV2.1 currents can be reduced in some cell types in Ca IM-AA mice•CaV2.1 facilitation offsets inactivation to maintain constant calcium entry Activation of CaV2.1 voltage-gated calcium channels is facilitated by preceding calcium entry. Such self-modulatory facilitation is thought to contribute to synaptic facilitation. Using knockin mice with mutated CaV2.1 channels that do not facilitate (Ca IM-AA mice), we surprisingly found that, under conditions of physiological calcium and near-physiological temperatures, synaptic facilitation at hippocampal CA3 to CA1 synapses was not attenuated in Ca IM-AA mice and facilitation was paradoxically more prominent at two cerebellar synapses. Enhanced facilitation at these synapses is consistent with a decrease in initial calcium entry, suggested by an action-potential-evoked CaV2.1 current reduction in Purkinje cells from Ca IM-AA mice. In wild-type mice, CaV2.1 facilitation during high-frequency action potential trains was very small. Thus, for the synapses studied, facilitation of calcium entry through CaV2.1 channels makes surprisingly little contribution to synaptic facilitation under physiological conditions. Instead, CaV2.1 facilitation offsets CaV2.1 inactivation to produce remarkably stable calcium influx during high-frequency activation. Activation of CaV2.1 voltage-gated calcium channels is facilitated by preceding calcium entry. Such self-modulatory facilitation is thought to contribute to synaptic facilitation. Using knockin mice with mutated CaV2.1 channels that do not facilitate (Ca IM-AA mice), we surprisingly found that, under conditions of physiological calcium and near-physiological temperatures, synaptic facilitation at hippocampal CA3 to CA1 synapses was not attenuated in Ca IM-AA mice and facilitation was paradoxically more prominent at two cerebellar synapses. Enhanced facilitation at these synapses is consistent with a decrease in initial calcium entry, suggested by an action-potential-evoked CaV2.1 current reduction in Purkinje cells from Ca IM-AA mice. In wild-type mice, CaV2.1 facilitation during high-frequency action potential trains was very small. Thus, for the synapses studied, facilitation of calcium entry through CaV2.1 channels makes surprisingly little contribution to synaptic facilitation under physiological conditions. Instead, CaV2.1 facilitation offsets CaV2.1 inactivation to produce remarkably stable calcium influx during high-frequency activation. Synaptic facilitation is a widespread form of use-dependent enhancement of neurotransmitter release that lasts for hundreds of milliseconds (Zucker and Regehr, 2002Zucker R.S. Regehr W.G. Short-term synaptic plasticity.Annu. Rev. Physiol. 2002; 64: 355-405Crossref PubMed Scopus (3224) Google Scholar). Facilitation can counteract depression (Turecek et al., 2016Turecek J. Jackman S.L. Regehr W.G. Synaptic specializations support frequency-independent Purkinje Cell output from the cerebellar cortex.Cell Rep. 2016; 17: 3256-3268Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, Turecek et al., 2017Turecek J. Jackman S.L. Regehr W.G. Synaptotagmin 7 confers frequency invariance onto specialized depressing synapses.Nature. 2017; 551: 503-506Crossref PubMed Scopus (45) Google Scholar), act as a temporal filter (Abbott and Regehr, 2004Abbott L.F. Regehr W.G. Synaptic computation.Nature. 2004; 431: 796-803Crossref PubMed Scopus (1142) Google Scholar), is implicated in working memory (Itskov et al., 2011Itskov V. Hansel D. Tsodyks M. Short-term facilitation may stabilize parametric working memory trace.Front. Comput. Neurosci. 2011; 5: 40Crossref PubMed Scopus (72) Google Scholar, Mongillo et al., 2008Mongillo G. Barak O. Tsodyks M. Synaptic theory of working memory.Science. 2008; 319: 1543-1546Crossref PubMed Scopus (702) Google Scholar), and has been proposed to serve many other functional roles (Jackman and Regehr, 2017Jackman S.L. Regehr W.G. The mechanisms and functions of synaptic facilitation.Neuron. 2017; 94: 447-464Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar). Multiple mechanisms have been suggested to account for synaptic facilitation (Jackman and Regehr, 2017Jackman S.L. Regehr W.G. The mechanisms and functions of synaptic facilitation.Neuron. 2017; 94: 447-464Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar), including local saturation of calcium buffer (Blatow et al., 2003Blatow M. Caputi A. Burnashev N. Monyer H. Rozov A. Ca2+ buffer saturation underlies paired pulse facilitation in calbindin-D28k-containing terminals.Neuron. 2003; 38: 79-88Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, Rozov et al., 2001Rozov A. Burnashev N. Sakmann B. Neher E. Transmitter release modulation by intracellular Ca2+ buffers in facilitating and depressing nerve terminals of pyramidal cells in layer 2/3 of the rat neocortex indicates a target cell-specific difference in presynaptic calcium dynamics.J. Physiol. 2001; 531: 807-826Crossref PubMed Scopus (309) Google Scholar), a specialized high-affinity calcium sensor such as synaptotagmin 7 (Jackman et al., 2016Jackman S.L. Turecek J. Belinsky J.E. Regehr W.G. The calcium sensor synaptotagmin 7 is required for synaptic facilitation.Nature. 2016; 529: 88-91Crossref PubMed Scopus (182) Google Scholar), and facilitation of calcium entry through voltage-gated calcium channels (Mochida et al., 2008Mochida S. Few A.P. Scheuer T. Catterall W.A. Regulation of presynaptic Ca(V)2.1 channels by Ca2+ sensor proteins mediates short-term synaptic plasticity.Neuron. 2008; 57: 210-216Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, Nanou and Catterall, 2018Nanou E. Catterall W.A. Calcium channels, synaptic plasticity, and neuropsychiatric disease.Neuron. 2018; 98: 466-481Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, Nanou et al., 2016aNanou E. Sullivan J.M. Scheuer T. Catterall W.A. Calcium sensor regulation of the CaV2.1 Ca2+ channel contributes to short-term synaptic plasticity in hippocampal neurons.Proc. Natl. Acad. Sci. USA. 2016; 113: 1062-1067Crossref PubMed Scopus (28) Google Scholar). Alterations in calcium entry have long been of special interest as a means of regulating neurotransmitter release, because at most synapses, release is highly sensitive to small changes in calcium entry (Dodge and Rahamimoff, 1967Dodge Jr., F.A. Rahamimoff R. Co-operative action a calcium ions in transmitter release at the neuromuscular junction.J. Physiol. 1967; 193: 419-432Crossref PubMed Scopus (918) Google Scholar, Katz and Miledi, 1968Katz B. Miledi R. The role of calcium in neuromuscular facilitation.J. Physiol. 1968; 195: 481-492Crossref PubMed Scopus (919) Google Scholar). Typically, release varies as (Cainflux)4 such that a 20% increase in Cainflux doubles synaptic strength (Cuttle et al., 1998Cuttle M.F. Tsujimoto T. Forsythe I.D. Takahashi T. Facilitation of the presynaptic calcium current at an auditory synapse in rat brainstem.J. Physiol. 1998; 512: 723-729Crossref PubMed Scopus (152) Google Scholar, Díaz-Rojas et al., 2015Díaz-Rojas F. Sakaba T. Kawaguchi S.Y. Ca(2+) current facilitation determines short-term facilitation at inhibitory synapses between cerebellar Purkinje cells.J. Physiol. 2015; 593: 4889-4904Crossref PubMed Scopus (13) Google Scholar, Dodge and Rahamimoff, 1967Dodge Jr., F.A. Rahamimoff R. Co-operative action a calcium ions in transmitter release at the neuromuscular junction.J. Physiol. 1967; 193: 419-432Crossref PubMed Scopus (918) Google Scholar, Neher and Sakaba, 2008Neher E. Sakaba T. Multiple roles of calcium ions in the regulation of neurotransmitter release.Neuron. 2008; 59: 861-872Abstract Full Text Full Text PDF PubMed Scopus (621) Google Scholar). Most types of calcium channels exhibit calcium-dependent inactivation (Ben-Johny and Yue, 2014Ben-Johny M. Yue D.T. Calmodulin regulation (calmodulation) of voltage-gated calcium channels.J. Gen. Physiol. 2014; 143: 679-692Crossref PubMed Scopus (141) Google Scholar, Catterall and Few, 2008Catterall W.A. Few A.P. Calcium channel regulation and presynaptic plasticity.Neuron. 2008; 59: 882-901Abstract Full Text Full Text PDF PubMed Scopus (489) Google Scholar, Christel and Lee, 2012Christel C. Lee A. Ca2+-dependent modulation of voltage-gated Ca2+ channels.Biochim. Biophys. Acta. 2012; 1820: 1243-1252Crossref PubMed Scopus (82) Google Scholar). However, CaV2.1 channels, which play a crucial role in transmission at many synapses, can exhibit use-dependent facilitation of calcium current (Ben-Johny and Yue, 2014Ben-Johny M. Yue D.T. Calmodulin regulation (calmodulation) of voltage-gated calcium channels.J. Gen. Physiol. 2014; 143: 679-692Crossref PubMed Scopus (141) Google Scholar, Christel and Lee, 2012Christel C. Lee A. Ca2+-dependent modulation of voltage-gated Ca2+ channels.Biochim. Biophys. Acta. 2012; 1820: 1243-1252Crossref PubMed Scopus (82) Google Scholar, Cuttle et al., 1998Cuttle M.F. Tsujimoto T. Forsythe I.D. Takahashi T. Facilitation of the presynaptic calcium current at an auditory synapse in rat brainstem.J. Physiol. 1998; 512: 723-729Crossref PubMed Scopus (152) Google Scholar, Inchauspe et al., 2004Inchauspe C.G. Martini F.J. Forsythe I.D. Uchitel O.D. Functional compensation of P/Q by N-type channels blocks short-term plasticity at the calyx of Held presynaptic terminal.J. Neurosci. 2004; 24: 10379-10383Crossref PubMed Scopus (115) Google Scholar, Lee et al., 2000Lee A. Scheuer T. Catterall W.A. Ca2+/calmodulin-dependent facilitation and inactivation of P/Q-type Ca2+ channels.J. Neurosci. 2000; 20: 6830-6838Crossref PubMed Google Scholar, Liang et al., 2003Liang H. DeMaria C.D. Erickson M.G. Mori M.X. Alseikhan B.A. Yue D.T. Unified mechanisms of Ca2+ regulation across the Ca2+ channel family.Neuron. 2003; 39: 951-960Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar). Calmodulin (CaM) is crucially involved in CaV2.1 channel facilitation (Lee et al., 1999Lee A. Wong S.T. Gallagher D. Li B. Storm D.R. Scheuer T. Catterall W.A. Ca2+/calmodulin binds to and modulates P/Q-type calcium channels.Nature. 1999; 399: 155-159Crossref PubMed Scopus (1002) Google Scholar, Lee et al., 2000Lee A. Scheuer T. Catterall W.A. Ca2+/calmodulin-dependent facilitation and inactivation of P/Q-type Ca2+ channels.J. Neurosci. 2000; 20: 6830-6838Crossref PubMed Google Scholar). CaM pre-associates with CaV2.1 channels (Erickson et al., 2001Erickson M.G. Alseikhan B.A. Peterson B.Z. Yue D.T. Preassociation of calmodulin with voltage-gated Ca(2+) channels revealed by FRET in single living cells.Neuron. 2001; 31: 973-985Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar), and upon Ca2+ binding to its C terminus (DeMaria et al., 2001DeMaria C.D. Soong T.W. Alseikhan B.A. Alvania R.S. Yue D.T. Calmodulin bifurcates the local Ca2+ signal that modulates P/Q-type Ca2+ channels.Nature. 2001; 411: 484-489Crossref PubMed Scopus (338) Google Scholar), it interacts with the IQ-like motif (IM) containing the amino acids isoleucine (I) and methionine (M) (DeMaria et al., 2001DeMaria C.D. Soong T.W. Alseikhan B.A. Alvania R.S. Yue D.T. Calmodulin bifurcates the local Ca2+ signal that modulates P/Q-type Ca2+ channels.Nature. 2001; 411: 484-489Crossref PubMed Scopus (338) Google Scholar, Lee et al., 2003Lee A. Zhou H. Scheuer T. Catterall W.A. Molecular determinants of Ca(2+)/calmodulin-dependent regulation of Ca(v)2.1 channels.Proc. Natl. Acad. Sci. USA. 2003; 100: 16059-16064Crossref PubMed Scopus (131) Google Scholar). Changing these amino acids to alanines (IM-AA) abolishes CaV2.1 channel facilitation (DeMaria et al., 2001DeMaria C.D. Soong T.W. Alseikhan B.A. Alvania R.S. Yue D.T. Calmodulin bifurcates the local Ca2+ signal that modulates P/Q-type Ca2+ channels.Nature. 2001; 411: 484-489Crossref PubMed Scopus (338) Google Scholar, Lee et al., 2003Lee A. Zhou H. Scheuer T. Catterall W.A. Molecular determinants of Ca(2+)/calmodulin-dependent regulation of Ca(v)2.1 channels.Proc. Natl. Acad. Sci. USA. 2003; 100: 16059-16064Crossref PubMed Scopus (131) Google Scholar, Zühlke et al., 2000Zühlke R.D. Pitt G.S. Tsien R.W. Reuter H. Ca2+-sensitive inactivation and facilitation of L-type Ca2+ channels both depend on specific amino acid residues in a consensus calmodulin-binding motif in the(α)1C subunit.J. Biol. Chem. 2000; 275: 21121-21129Crossref PubMed Scopus (155) Google Scholar) (Figure 1A, left). Because of the sensitivity of transmitter release to small changes in calcium entry, it is expected that calcium-dependent facilitation of calcium entry through CaV2.1 channels should produce synaptic facilitation. Indeed, at the calyx of Held synapse (Borst and Sakmann, 1998Borst J.G.G. Sakmann B. Facilitation of presynaptic calcium currents in the rat brainstem.J. Physiol. 1998; 513: 149-155Crossref PubMed Scopus (134) Google Scholar, Cuttle et al., 1998Cuttle M.F. Tsujimoto T. Forsythe I.D. Takahashi T. Facilitation of the presynaptic calcium current at an auditory synapse in rat brainstem.J. Physiol. 1998; 512: 723-729Crossref PubMed Scopus (152) Google Scholar), as well as at synapses between cultured Purkinje cells (PCs) (Díaz-Rojas et al., 2015Díaz-Rojas F. Sakaba T. Kawaguchi S.Y. Ca(2+) current facilitation determines short-term facilitation at inhibitory synapses between cerebellar Purkinje cells.J. Physiol. 2015; 593: 4889-4904Crossref PubMed Scopus (13) Google Scholar), synaptic facilitation was accompanied by use-dependent increases in presynaptic calcium currents. The finding that calcium current facilitation was eliminated and synaptic facilitation was strongly attenuated in CaV2.1 knockout (KO) mice at the calyx of Held (Inchauspe et al., 2004Inchauspe C.G. Martini F.J. Forsythe I.D. Uchitel O.D. Functional compensation of P/Q by N-type channels blocks short-term plasticity at the calyx of Held presynaptic terminal.J. Neurosci. 2004; 24: 10379-10383Crossref PubMed Scopus (115) Google Scholar, Ishikawa et al., 2005Ishikawa T. Kaneko M. Shin H.S. Takahashi T. Presynaptic N-type and P/Q-type Ca2+ channels mediating synaptic transmission at the calyx of Held of mice.J. Physiol. 2005; 568: 199-209Crossref PubMed Scopus (99) Google Scholar) supported a central role for CaV2.1 in synaptic facilitation. Similarly, synaptic transmission between cultured superior cervical ganglion (SCG) neurons is normally mediated by non-facilitating CaV2.2 channels, and these synapses do not facilitate (Ben-Johny and Yue, 2014Ben-Johny M. Yue D.T. Calmodulin regulation (calmodulation) of voltage-gated calcium channels.J. Gen. Physiol. 2014; 143: 679-692Crossref PubMed Scopus (141) Google Scholar, Liang et al., 2003Liang H. DeMaria C.D. Erickson M.G. Mori M.X. Alseikhan B.A. Yue D.T. Unified mechanisms of Ca2+ regulation across the Ca2+ channel family.Neuron. 2003; 39: 951-960Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar, Nanou and Catterall, 2018Nanou E. Catterall W.A. Calcium channels, synaptic plasticity, and neuropsychiatric disease.Neuron. 2018; 98: 466-481Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar). However, upon expression of CaV2.1 channels and subsequent blockade of CaV2.2 channels in SCG neurons, CaV2.1 channels facilitated along with synaptic transmission. In contrast, the expression of non-facilitating mutated IM-AA CaV2.1 channels led to strongly reduced facilitation of SCG synapses (Mochida et al., 2003Mochida S. Westenbroek R.E. Yokoyama C.T. Itoh K. Catterall W.A. Subtype-selective reconstitution of synaptic transmission in sympathetic ganglion neurons by expression of exogenous calcium channels.Proc. Natl. Acad. Sci. USA. 2003; 100: 2813-2818Crossref PubMed Scopus (63) Google Scholar, Mochida et al., 2008Mochida S. Few A.P. Scheuer T. Catterall W.A. Regulation of presynaptic Ca(V)2.1 channels by Ca2+ sensor proteins mediates short-term synaptic plasticity.Neuron. 2008; 57: 210-216Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar). Ca IM-AA knockin mice, in which CaV2.1 channels are replaced by mutated IM-AA CaV2.1 channels, are a powerful tool for testing the contribution of CaV2.1 facilitation to synaptic facilitation (Nanou et al., 2016bNanou E. Yan J. Whitehead N.P. Kim M.J. Froehner S.C. Scheuer T. Catterall W.A. Altered short-term synaptic plasticity and reduced muscle strength in mice with impaired regulation of presynaptic CaV2.1 Ca2+ channels.Proc. Natl. Acad. Sci. USA. 2016; 113: 1068-1073Crossref PubMed Scopus (8) Google Scholar, Nanou et al., 2016aNanou E. Sullivan J.M. Scheuer T. Catterall W.A. Calcium sensor regulation of the CaV2.1 Ca2+ channel contributes to short-term synaptic plasticity in hippocampal neurons.Proc. Natl. Acad. Sci. USA. 2016; 113: 1062-1067Crossref PubMed Scopus (28) Google Scholar, Nanou et al., 2018Nanou E. Lee A. Catterall W.A. Control of excitation/inhibition balance in a hippocampal circuit by calcium sensor protein regulation of presynaptic calcium channels.J. Neurosci. 2018; 38: 4430-4440Crossref PubMed Scopus (15) Google Scholar). Synaptic facilitation was eliminated or attenuated at some synapses in Ca IM-AA mice, suggesting that facilitation of CaV2.1 channels can account for a significant fraction of synaptic facilitation at the neuromuscular junction (NMJ), CA3 to CA1 (CA3-CA1), and CA3 to parvalbumin-expressing (PV) basket cell synapses (Nanou et al., 2016bNanou E. Yan J. Whitehead N.P. Kim M.J. Froehner S.C. Scheuer T. Catterall W.A. Altered short-term synaptic plasticity and reduced muscle strength in mice with impaired regulation of presynaptic CaV2.1 Ca2+ channels.Proc. Natl. Acad. Sci. USA. 2016; 113: 1068-1073Crossref PubMed Scopus (8) Google Scholar, Nanou et al., 2016aNanou E. Sullivan J.M. Scheuer T. Catterall W.A. Calcium sensor regulation of the CaV2.1 Ca2+ channel contributes to short-term synaptic plasticity in hippocampal neurons.Proc. Natl. Acad. Sci. USA. 2016; 113: 1062-1067Crossref PubMed Scopus (28) Google Scholar, Nanou et al., 2018Nanou E. Lee A. Catterall W.A. Control of excitation/inhibition balance in a hippocampal circuit by calcium sensor protein regulation of presynaptic calcium channels.J. Neurosci. 2018; 38: 4430-4440Crossref PubMed Scopus (15) Google Scholar). However, many factors can influence short-term synaptic plasticity, and the contribution of CaV2.1 channel facilitation to synaptic facilitation under physiological conditions of temperature and external calcium (Caext) with calcium entry during action potential waveforms is still unclear. Quantification of facilitation of voltage-clamped CaV2.1 channels has mostly been performed at room temperature, often using voltage steps lasting longer than action potentials and with relatively high Caext. Temperature is a crucial factor, because action potential width, calcium channel activation kinetics, and kinetics of protein-protein interactions are all strongly temperature dependent. Prolonged voltage steps and high Caext may tend to increase the extent of CaV2.1 channel facilitation. Many previous studies characterizing CaV2.1 channel facilitation in synaptic facilitation were performed in the presence of CaV2.2 antagonists to isolate effects on CaV2.1 channels. However, inhibiting calcium entry through CaV2.2 channels could potentially modify many calcium-dependent processes in presynaptic terminals and decrease the initial probability of release. In addition, at many synapses, the deletion of synaptotagmin 7 eliminates synaptic facilitation, even though this should not affect calcium channel facilitation and does not produce alterations in presynaptic calcium signals (Jackman et al., 2016Jackman S.L. Turecek J. Belinsky J.E. Regehr W.G. The calcium sensor synaptotagmin 7 is required for synaptic facilitation.Nature. 2016; 529: 88-91Crossref PubMed Scopus (182) Google Scholar). We therefore assessed the contribution of CaV2.1 facilitation to synaptic facilitation under conditions of physiological Caext (1.5 mM) at near-physiological temperatures and in the absence of CaV2.2 blockers. Under these conditions, we unexpectedly found that synaptic facilitation at three different synapses was not attenuated in Ca IM-AA mice. Also, under similar conditions of temperature and Caext, wild-type (WT) CaV2.1 channel facilitation surprisingly was very small. We therefore conclude that at the synapses we tested, CaV2.1 channel facilitation makes surprisingly little contribution to synaptic facilitation under conditions of physiological Caext and temperature and may instead serve primarily to counteract calcium channel inactivation. In order to determine the role of facilitation of calcium entry in synaptic transmission, we studied knockin mice (Ca IM-AA mice) in which WT CaV2.1 calcium channels are replaced by CaV2.1 calcium channels containing an IM that has been mutated to prevent calcium-dependent facilitation of calcium entry (DeMaria et al., 2001DeMaria C.D. Soong T.W. Alseikhan B.A. Alvania R.S. Yue D.T. Calmodulin bifurcates the local Ca2+ signal that modulates P/Q-type Ca2+ channels.Nature. 2001; 411: 484-489Crossref PubMed Scopus (338) Google Scholar, Lee et al., 2003Lee A. Zhou H. Scheuer T. Catterall W.A. Molecular determinants of Ca(2+)/calmodulin-dependent regulation of Ca(v)2.1 channels.Proc. Natl. Acad. Sci. USA. 2003; 100: 16059-16064Crossref PubMed Scopus (131) Google Scholar, Mochida et al., 2008Mochida S. Few A.P. Scheuer T. Catterall W.A. Regulation of presynaptic Ca(V)2.1 channels by Ca2+ sensor proteins mediates short-term synaptic plasticity.Neuron. 2008; 57: 210-216Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, Nanou et al., 2016aNanou E. Sullivan J.M. Scheuer T. Catterall W.A. Calcium sensor regulation of the CaV2.1 Ca2+ channel contributes to short-term synaptic plasticity in hippocampal neurons.Proc. Natl. Acad. Sci. USA. 2016; 113: 1062-1067Crossref PubMed Scopus (28) Google Scholar) (Figure 1A, left). We initially characterized the properties of calcium entry in acutely dissociated PCs using conditions similar to those used previously (30 stimuli at 100 Hz, 5-ms voltage steps at room temperature in 10 mM external Ca2+). Maximal use-dependent facilitation of calcium currents of ∼19% was apparent in WT mice, which was replaced by maximal use-dependent depression of ∼26% in Ca IM-AA mice (Figure 1A, right; Table S1). These findings confirm that calcium-dependent facilitation of CaV2.1 calcium channels in cerebellar Purkinje neurons is eliminated in Ca IM-AA mice, as described previously for CaV2.1 channels in SCG and hippocampal neurons (Mochida et al., 2008Mochida S. Few A.P. Scheuer T. Catterall W.A. Regulation of presynaptic Ca(V)2.1 channels by Ca2+ sensor proteins mediates short-term synaptic plasticity.Neuron. 2008; 57: 210-216Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, Nanou et al., 2016aNanou E. Sullivan J.M. Scheuer T. Catterall W.A. Calcium sensor regulation of the CaV2.1 Ca2+ channel contributes to short-term synaptic plasticity in hippocampal neurons.Proc. Natl. Acad. Sci. USA. 2016; 113: 1062-1067Crossref PubMed Scopus (28) Google Scholar). They also illustrate how calcium-dependent facilitation can serve to offset calcium-dependent inactivation in Cav2.1 channels in native neurons. We then sought to determine the extent to which facilitation of calcium entry contributes to facilitation of synaptic transmission in physiological Caext (1.5 mM) at 33°C–36°C in the absence of CaV2.2 channel antagonists. We performed experiments in the presence of GABAA receptor blockers to better isolate excitatory postsynaptic currents (EPSCs) for quantification and also in the presence of GABAB receptor blockers to avoid confounding changes in synaptic strength resulting from GABAB-mediated presynaptic inhibition, especially during trains. To obtain a more complete picture of the role of CaV2.1 facilitation in synaptic facilitation, we studied three types of synapses with diverse properties. We used acute brain slices and stimulated synaptic inputs with pairs of pulses separated by different inter-stimulus intervals (ISIs) to determine paired-pulse plasticity of the postsynaptic currents (PSCs). Contrary to the expectation that synaptic facilitation would be attenuated in Ca IM-AA mice, at hippocampal CA3-CA1 synapses, the amplitudes and decays of exponential fits were not statistically significantly different in WT and Ca IM-AA mice (Figure 1B; Table S1). Even more surprisingly, synaptic facilitation was actually enhanced in the Ca IM-AA mice at the cerebellar parallel fiber to PC (PF-PC) synapse. In WT animals, the paired-pulse ratio (PPR) peaked at 10 ms with a 2.7-fold increase and decayed with a time constant of 47 ms. In Ca IM-AA mice, the maximal mean PPR was virtually identical for short ISIs (2.8-fold at 10 ms), but facilitation was longer lived and decayed with a time constant of 85 ms. While the amplitudes of the exponential facilitation fit are not significantly different, the decay time constants are significantly different (Figure 1C; Table S1). Thus, unexpectedly, facilitation is actually larger in Ca IM-AA mice than in WT mice at PF-PC synapses for some ISIs. The results were even more surprising at the PC to deep cerebellar nuclei (PC-DCN) synapse. Short-term plasticity at this synapse is complicated and consists of a combination of facilitation and depression (Turecek et al., 2016Turecek J. Jackman S.L. Regehr W.G. Synaptic specializations support frequency-independent Purkinje Cell output from the cerebellar cortex.Cell Rep. 2016; 17: 3256-3268Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, Turecek et al., 2017Turecek J. Jackman S.L. Regehr W.G. Synaptotagmin 7 confers frequency invariance onto specialized depressing synapses.Nature. 2017; 551: 503-506Crossref PubMed Scopus (45) Google Scholar). In 1.5 mM Caext, the initial probability of release is sufficiently high that depression dominates the PPR in WT animals. Surprisingly, in PC-DCN synapses of Ca IM-AA mice, synaptic facilitation was prominent, whereas in WT mice, synaptic depression dominated (Figure 1D; Table S1). Thus, at all three synapses tested, two glutamatergic and one GABAergic, the maximal paired-pulse facilitation (PPF) was either the same or larger in Ca IM-AA mice in 1.5 mM Caext at near-physiological temperatures. Neurons often fire in bursts under physiological conditions. We therefore examined short-term plasticity during synaptic activation consisting of ten electrical pulses at different frequencies using a similar approach and experimental conditions used to study paired-pulse plasticity (Figures 2). For WT mice at hippocampal CA3-CA1 synapse, synaptic enhancement plateaued at 2- to 3-fold and the extent of synaptic enhancement was frequency dependent (Figure 2A, black; Table S1). The maximal train facilitation and frequency dependence of synaptic enhancement was unaltered in Ca IM-AA mice (Figure 2A, red; Table S1). For the PF-PC synapse in WT mice, the synaptic enhancement reached 3-fold, and the extent of synaptic enhancement was also frequency dependent (Figure 2B, black; Table S1). We found, however, that the maximal enhancement of PF-PC synapses was significantly larger in Ca IM-AA mice during trains (up to 4-fold), which is consistent with the prolonged decay of PPF in Ca IM-AA mice (Figure 1C; Table S1). A different approach was required for the PC-DCN synapse. PCs fire spontaneously at frequencies of 10 Hz to over 100 Hz, and therefore, sustained synaptic activation is more physiologically relevant. WT PC-DCN synapses depress until they reach a steady-state amplitude (Turecek et al., 2016Turecek J. Jackman S.L. Regehr W.G. Synaptic specializations support frequency-independent Purkinje Cell output from the cerebellar cortex.Cell Rep. 2016; 17: 3256-3268Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, Turecek et al., 2017Turecek J. Jackman S.L. Regehr W.G. Synaptotagmin 7 confers frequency invariance onto specialized depressing synapses.Nature. 2017; 551: 503-506Crossref PubMed Scopus (45) Google Scholar) (Figures 3A, 3B, and 3E , black; Table S1). At most depressing synapses, steady-state amplitudes are smaller as the frequency of activation is increased, but at PC-DCN synapses, this is not the case, and steady-state amplitudes of the PC-DCN synapse are frequency invariant over a broad range of stimulus frequencies in WT animals (Figure 3B, black). Even though depression dominates short-term plasticity during trains, the net plasticity reflects a combination of facilitation and depression, and facilitation is essential for the frequency invariance of this synapse. The elimination of facilitation is predicted to lead to a frequency-dependent synapse (Turecek et al., 2017Turecek J. Jackman S.L. Regehr W.G. Synaptotagmin 7 confers frequency invariance onto specialized depressing synapses.Nature. 2017; 551: 503-506Crossref PubMed Scopus (45) Google Scholar). However, this was not the case. In Ca IM-AA mice, synaptic responses facilitated slightly at the start of stimulation and responses reached steady-state levels that were elevated relative to WT animals, but steady-state responses remained frequency invariant (Figures 3A and 3E). Facilitation can be studied more directly by stimulating with 10-Hz trains and abruptly increasing the stimulus frequency to 100 Hz (Figures 3C and 3D, black; Table S1). Facilitation was actually much more prominent in Ca IM-AA mice than in WT mice. Thus, synaptic responses evoked by stimulus trains are inconsistent with responses predicted to occur if facilitation of influx through CaV2.1 is the primary mechanism of facilitation. The larger synaptic facilitation in Ca" @default.
• W2917681567 created "2019-03-02" @default.
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• W2917681567 creator A5053791142 @default.
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• W2917681567 date "2019-02-01" @default.
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• W2917681567 title "The Role of CaV2.1 Channel Facilitation in Synaptic Facilitation" @default.
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