title: Lithium: a switch from LTD- to LTP-like plasticity in human cortex.
abstract: Lithium, a simple cation, is the mainstay treatment of bipolar disorder. Deficient synaptic plasticity is considered one important mechanism of this disease. Lithium inhibits glycogen synthase kinase-3beta (GSK-3β), which is involved in the regulation of synaptic plasticity. In animal preparations, inhibition of GSK-3β by lithium up-regulated long-term potentiation (LTP) of excitatory synapses but down-regulated long-term depression (LTD). The effects of lithium on plasticity in the human brain are unexplored. We tested the effects of a single oral dose of 900 mg of lithium on LTP-/LTD-like plasticity in human motor cortex induced by established paired associative transcranial magnetic stimulation (PAS(LTP), PAS(LTD)) protocols. We studied 10 healthy adults in a placebo-controlled double-blind randomized crossover design. PAS-induced plasticity was indexed by change in motor evoked potential amplitude recorded in a hand muscle. In the placebo session, subjects were stratified, according to the known variability of the PAS(LTP) response, into PAS(LTP) 'LTP responders' and PAS(LTP) 'LTD responders' (n = 5 each). Lithium did not affect the PAS(LTP)-induced LTP-like plasticity in the 'LTP responders', but switched the PAS(LTP)-induced LTD-like plasticity in the 'LTD responders' to LTP-like plasticity. In contrast, lithium had no effect on the PAS(LTD)-induced LTD-like plasticity in the 'LTD responders'. We provide first-time evidence that lithium significantly modulates brain stimulation induced plasticity in human cortex. The switch from LTD- to LTP-like plasticity is best explained by the inhibitory action of lithium on GSK-3β. This conclusion is necessarily circumstantial because GSK-3β activity was not directly measured. We discuss that other important plasticity-related modes actions of lithium cannot explain our findings.
authors.affiliation: Department of Neurology, Goethe-University Frankfurt, Schleusenweg 2-16, D-60528 Frankfurt am Main, Germany.
authors.forename: Hanna
authors.initials: H
authors.lastname: Voytovych
authors.forename: Lucia
authors.initials: L
authors.lastname: Kriváneková
authors.forename: Ulf
authors.initials: U
authors.lastname: Ziemann
mesh_terms: D000328:Adult; D018592:Cross-Over Studies; D004311:Double-Blind Method; D019054:Evoked Potentials, Motor / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006225:Hand / Q000502:physiology; D006801:Humans; D018020:Lithium Compounds / Q000494:pharmacology*; 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; D009068:Movement / Q000502:physiology; D009473:Neuronal Plasticity; D050781:Transcranial Magnetic Stimulation; D055815:Young Adult
chemical_list: D018020:Lithium Compounds