title: L-type voltage-gated Ca2+ channels: a single molecular switch for long-term potentiation/long-term depression-like plasticity and activity-dependent metaplasticity in humans.
abstract: The ability of synapses to undergo persistent activity-dependent potentiation or depression [long-term potentiation (LTP)/long-term depression (LTD)] may be profoundly altered by previous neuronal activity. Although natural neuronal activity can be experimentally manipulated in vivo, very little is known about the in vivo physiological mechanisms involved in regulating this metaplasticity in models of LTP/LTD. To examine whether Ca(2+) signaling may influence metaplasticity in vivo in humans, we used continuous theta burst stimulation (cTBS) (Huang et al., 2005), a noninvasive novel repetitive magnetic stimulation protocol known to induce persistent alterations of corticospinal excitability whose polarity is changed by previous voluntary motor activity. When directed to the naive motor cortex, cTBS induced long-lasting potentiation of corticospinal excitability, but depression under the influence of nimodipine (NDP), an L-type voltage-gated Ca(2+) channel (L-VGCC) antagonist. Both aftereffects were blocked by dextromethorphan, an NMDA receptor antagonist, supporting the notion that these bidirectional cTBS-induced alterations of corticospinal excitability map onto LTP and LTD as observed in animal studies. A short period of voluntary contraction and a small dose of NDP were each ineffective in blocking the cTBS-induced potentiation. However, when both interventions were combined, a depression was induced, and the magnitude of this depression increased with the dose of NDP. These findings suggest that Ca(2+) dynamics determine the polarity of LTP/LTD-like changes in vivo. L-VGCCs may act as molecular switches mediating metaplasticity induced by endogenous neuronal activation.
authors.affiliation: Human Cortical Physiology and Motor Control Laboratory, Department of Neurology, University of Wuerzburg, D-97080 Wuerzburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Wankerl
authors.forename: David
authors.initials: D
authors.lastname: Weise
authors.forename: Reinhard
authors.initials: R
authors.lastname: Gentner
authors.forename: Jost-Julian
authors.initials: JJ
authors.lastname: Rumpf
authors.forename: Joseph
authors.initials: J
authors.lastname: Classen
mesh_terms: D000328:Adult; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology*; D003915:Dextromethorphan / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D019054:Evoked Potentials, Motor / Q000187:drug effects / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D006801:Humans; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009044:Motor Cortex / Q000187:drug effects / Q000502:physiology; D009119:Muscle Contraction / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009553:Nimodipine / Q000494:pharmacology; D011712:Pyramidal Tracts / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D050781:Transcranial Magnetic Stimulation
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D018691:Excitatory Amino Acid Antagonists; D009553:Nimodipine; D003915:Dextromethorphan
references.citation: Nature. 1990 Sep 6;347(6288):69-72
references.pmid: 1975639
references.citation: Exp Brain Res. 1991;85(3):621-4
references.pmid: 1680738
references.citation: Clin Neurophysiol. 2007 May;118(5):1028-32
references.pmid: 17368094
references.citation: J Neurosci. 1998 Dec 15;18(24):10464-72
references.pmid: 9852584
references.citation: Neuron. 1992 Dec;9(6):1175-83
references.pmid: 1361129
references.citation: Nat Rev Neurosci. 2008 May;9(5):387
references.pmid: 18401345
references.citation: Neuron. 2005 Jan 20;45(2):201-6
references.pmid: 15664172
references.citation: Clin Neurophysiol. 2001 Feb;112(2):250-8
references.pmid: 11165526
references.citation: Eur J Neurosci. 2001 Aug;14(4):701-8
references.pmid: 11556894
references.citation: Prog Neurobiol. 2001 Nov;65(4):339-65
references.pmid: 11527572
references.citation: Physiol Rev. 2008 Apr;88(2):769-840
references.pmid: 18391179
references.citation: Eur J Pharmacol. 1993 Feb 16;231(3):355-61
references.pmid: 8449228
references.citation: Trends Neurosci. 2007 Apr;30(4):176-84
references.pmid: 17335914
references.citation: Nature. 1984 Oct 11-17;311(5986):538-44
references.pmid: 6207437
references.citation: Neurosci Res. 1996 Feb;24(3):265-74
references.pmid: 8815446
references.citation: Neuroreport. 1991 Jul;2(7):393-6
references.pmid: 1912472
references.citation: Curr Opin Neurobiol. 1996 Jun;6(3):331-7
references.pmid: 8794076
references.citation: Neuron. 2002 Dec 19;36(6):1103-14
references.pmid: 12495625
references.citation: N Engl J Med. 1983 Mar 17;308(11):619-24
references.pmid: 6338383
references.citation: Neurosci Lett. 1988 Feb 29;85(2):261-6
references.pmid: 2897648
references.citation: Neuron. 2007 Jan 18;53(2):249-60
references.pmid: 17224406
references.citation: Brain Stimul. 2008 Jul;1(3):151-63
references.pmid: 20633382
references.citation: Eur J Neurosci. 1997 Nov;9(11):2309-22
references.pmid: 9464925
references.citation: Neuron. 2003 Oct 9;40(2):331-46
references.pmid: 14556712
references.citation: Proc Natl Acad Sci U S A. 1989 Dec;86(23):9574-8
references.pmid: 2556718
references.citation: Neuron. 2007 Sep 20;55(6):919-29
references.pmid: 17880895
references.citation: Nat Rev Neurosci. 2008 May;9(5):357-69
references.pmid: 18425090
references.citation: Hippocampus. 1991 Apr;1(2):181-92
references.pmid: 1669292
references.citation: Nat Neurosci. 2004 Feb;7(2):126-35
references.pmid: 14730307
references.citation: Neuron. 1990 Jun;4(6):819-32
references.pmid: 2163262
references.citation: Trends Neurosci. 1993 Nov;16(11):480-7
references.pmid: 7507622
references.citation: J Neurosurg. 1996 May;84(5):860-6
references.pmid: 8622162
references.citation: Neuron. 1996 Apr;16(4):825-33
references.pmid: 8608000
references.citation: Brain Res. 1990 Oct 8;529(1-2):277-85
references.pmid: 2282497
references.citation: Nat Rev Neurosci. 2000 Dec;1(3):181-90
references.pmid: 11257906
references.citation: Nat Neurosci. 2009 Sep;12(9):1093-5
references.pmid: 19648911
references.citation: Neurosci Lett. 2009 Jan 16;449(3):220-3
references.pmid: 19010390
references.citation: Neuropharmacology. 1997 Jul;36(7):879-93
references.pmid: 9257934
references.citation: Eur J Pharm Sci. 2004 Mar;21(4):487-91
references.pmid: 14998579
references.citation: Ann Neurol. 1994 Dec;36(6):920-4
references.pmid: 7998781
references.citation: Science. 1987 Jan 2;235(4784):46-52
references.pmid: 2432656
references.citation: Neurology. 1998 Nov;51(5):1320-4
references.pmid: 9818853
references.citation: Cereb Cortex. 2008 Sep;18(9):2046-53
references.pmid: 18165282
references.citation: Annu Rev Neurosci. 2006;29:307-23
references.pmid: 16776588
references.citation: Nat Neurosci. 2003 Sep;6(9):948-55
references.pmid: 12937422
references.citation: Brain Res. 1986 Mar 19;368(2):347-50
references.pmid: 3697730
references.citation: Cell Calcium. 2005 Sep-Oct;38(3-4):355-67
references.pmid: 16154476
references.citation: Neuroreport. 1990 Sep;1(1):65-8
references.pmid: 2129860
references.citation: Science. 1994 May 13;264(5161):974-7
references.pmid: 8178157