Effects of Lithium on Plasticity in Human Motor Cortex Induced by Paired Associative Stimulation

Background: Lithium is widely used for the treatment of bipolar disorders. Relatively little is known about the CNS actions of lithium. One mode of action is that lithium inhibits the GSK–3ß kinase, an enzyme that in rat hippocampal slices mediates an interaction between two major forms of synaptic plasticity, i.e. long-term potentiation (LTP) and long-term depression (LTD). Inhibition of GSK–3ß favors LTP over LTD. Here we sought to examine the effects of a single oral dose of 900mg of lithium on LTP-like and LTD-like plasticity in human motor cortex, using established paired associative stimulation (PAS-LTP and PAS-LTD, respectively) protocols.

Methods: 10 healthy subjects each participated in a placebo-controlled double-blind randomized crossover design in either the PAS-LTP or PAS-LTD experiment. Motor evoked potential (MEP) amplitude were recorded from the right abductor pollicis brevis muscle before (time point B0) and 2 hours after drug intake (time point B1), and at six time points covering 30 min after PAS (time points P1-P6).

Results: Lithium per se had no significant effect on MEP amplitude (comparison of time points B1 and B0). Lithium had no effect on LTP-like plasticity (comparison of P1-P6 vs. B1) for the whole group of 10 subjects. However, division of the data into PAS-LTP responders (MEP facilitation) and PAS-LTP non-responders (MEP depression) showed that lithium had no effect on MEP facilitation but switched MEP depression to MEP facilitation. Lithium had no effect on PAS-LTD induced MEP depression.

Conclusion: PAS-LTP induces fragile LTP-like MEP facilitation. In subjects with PAS-LTP induced MEP depression lithium enhances the probability of induction of LTP-like MEP facilitation. Findings support the notion that, consistent with the data in hippocampal slices, GSK–3ß inhibition by lithium favors LTP-like over LTD-like plasticity at the level of human cortex.