Lithium modulates cortical excitability in vitro

The sometimes devastating mood swings of bipolar disorder are prevented by treatment with selected antiepileptic drugs, or with lithium. Abnormal membrane ion channel expression and excitability in brain neurons likely underlie bipolar disorder, but explaining therapeutic effects in these terms has faced an unresolved paradox: the antiepileptic drugs effective in bipolar disorder reduce Na+ entry through voltage-gated channels, but lithium freely enters neurons through them. Here we show that lithium increases the excitability of output neurons in brain slices of the mouse olfactory bulb, an archetypical cortical structure. Treatment in vitro with lithium (1 to 10 mM) depolarizes mitral cells, blocks action potential hyperpolarization, and modulates their responses to synaptic input. We suggest that Na+ entry through voltage-gated channels normally directly activates K+ channels regulating neuron excitability, but that at therapeutic concentrations, lithium entry and accumulation reduces this K+ channel activation. The antiepileptic drugs effective in bipolar disorder and lithium may thus share a membrane target consisting of functionally coupled Na+ and K+ channels that together control brain neuron excitability.

Research highlights
► Lithium increases cortical neuron membrane excitability.
► Lithium prevents activation of Na+-activated K+ channels.
► Lithium may act in bipolar disorder by influencing neuronal membrane potential.