Lithium: A switch from LTD- to LTP-like plasticity in human cortex

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 (PASLTP, PASLTD) 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 PASLTP response, into PASLTP ‘LTP responders’ and PASLTP ‘LTD responders’ (n = 5 each). Lithium did not affect the PASLTP-induced LTP-like plasticity in the ‘LTP responders’, but switched the PASLTP-induced LTD-like plasticity in the ‘LTD responders’ to LTP-like plasticity. In contrast, lithium had no effect on the PASLTD-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.

► Lithium increases the probability of LTP-like plasticity in human cortex.
► This effect is best explained by inhibition of GSK-3β by lithium.
► Data relate to bipolar disorder where GSK-3β overactivity has a pathogenetic role.