Calcium-abhängige Modulation neuronaler Plastizität beim Menschen
Final Report Abstract
The ability of synapses to undergo persistent activity-dependent potentiation or depression [longterm potentiation (LTP)/long-term depression (LTD)] may be profoundly altered by previous neuronal activity and Ca2+-signalling. Much of our knowledge about regulation of LTP/LTD has been obtained in slices and neuronal cell cultures, Although natural neuronal activity can be experimentally manipulated in vivo, very little is known about the in vivo physiological mechanisms involved. The present project asked how plasticity and activity-dependent metaplasticity is regulated in human models of LTP/LTD. A specific question asked was the role of Ca2+-channels in regulating plasticity induced by non-invasive brain stimulation. We used continuous theta burst stimulation (cTBS), a noninvasive repetitive magnetic stimulation protocol known to induce persistent alterations of corticospinal excitability whose polarity we had previously shown to depend on 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 Ca2+ 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 found to act synergistically in blocking the cTBS-induced potentiation. These findings suggested that Ca2+ 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. To characterize the role of Ca2+-signalling in plasticity induced by the non-invasive brain stimulation protocols paired associative stimulation (PAS) and cTBS , we examined the impact of different Ca2+-sources. PAS-induced facilitation of corticospinal excitability was blocked by NMDA-receptor blocker dextromethorphan (DXM) and L-type voltage gated Ca2+ channels (VGCC) blocker nimodipine (NDP), but turned into depression by T-type VGCC blocker ethosuximide (ESM). c TBS-induced facilitation of corticospinal excitability, was blocked, but not reverted, by T-type VGCC blocker ESM. The different patterns of Ca2+-channel modulation of PAS- and TBS- induced plasticity may point to an important role of backpropagating action potentials in PAS- induced plasticity, similar as in spike-timing dependent synaptic plasticity, and to a requirement of dendritic Ca2+-dependent spikes in TBS-induced plasticity. A model of how PAS and cTBS act on the motorcortical human microcircuit was generated.
Publications
- (2010): L-type voltage-gated Ca2+ channels. A single molecular switch for long-term potentiation/long-term depressionlike plasticity and activity-dependent metaplasticity in humans. The Journal of neuroscience : the official journal of the Society for Neuroscience 30 (18), pp. 6197–6204
Wankerl, Katharina; Weise, David; Gentner, Reinhard; Rumpf, Jost-Julian; Classen, Joseph
(See online at https://dx.doi.org/10.1523/JNEUROSCI.4673-09.2010) - (2013): A new temporal window for inducing depressant associative plasticity in human primary motor cortex. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology 124 (6), pp. 1196–1203
Schabrun, S. M.; Weise, D.; Ridding, M. C.; Classen, J.
(See online at https://doi.org/10.1016/j.clinph.2013.01.004) - (2013): Microcircuit mechanisms involved in paired associative stimulation-induced depression of corticospinal excitability. The Journal of Physiology 591 (19), pp. 4903–4920
Weise, David; Mann, Jakob; Ridding, Michael; Eskandar, Kevin; Huss, Martin; Rumpf, Jost-Julian et al.
(See online at https://doi.org/10.1113/jphysiol.2013.253989) - (2016): Differential Regulation of Human Paired Associative Stimulation-Induced and Theta-Burst Stimulation-Induced Plasticity by L-type and T-type Ca2+ Channels. Cerebral cortex (New York, N.Y. : 1991)
Weise, David; Mann, Jakob; Rumpf, Jost-Julian; Hallermann, Stefan; Classen, Joseph
(See online at https://dx.doi.org/10.1093/cercor/bhw212)
