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 10mM) 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.
Butler-Munro
Charlotte
C
Department of Physiology, University of Otago, Dunedin, New Zealand.
Coddington
Emma J
EJ
Shirley
Cristina H
CH
Heyward
Philip M
PM
D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology*; D005071:Evoked Potentials / Q000187:drug effects* / Q000502:physiology; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology; D007736:Kynurenic Acid / Q000494:pharmacology; D008094:Lithium / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009830:Olfactory Bulb / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D017470:Receptors, Glutamate / Q000187:drug effects* / Q000502:physiology
D000927:Anticonvulsants; D007473:Ion Channels; D015221:Potassium Channels; D017470:Receptors, Glutamate; D008094:Lithium; D007736:Kynurenic Acid