Premium
Lithium reduces the span of G protein‐activated K + ( GIRK ) channel inhibition in hippocampal neurons
Author(s) -
Dascal Nathan,
Rubinstein Moran
Publication year - 2017
Publication title -
bipolar disorders
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.285
H-Index - 129
eISSN - 1399-5618
pISSN - 1398-5647
DOI - 10.1111/bdi.12536
Subject(s) - g protein coupled inwardly rectifying potassium channel , hippocampal formation , chemistry , neuroscience , hyperpolarization (physics) , inhibitory postsynaptic potential , g protein , electrophysiology , potassium channel , biophysics , receptor , biology , biochemistry , organic chemistry , nuclear magnetic resonance spectroscopy
Objectives Lithium (Li + ) is one of the most widely used treatments for bipolar disorder ( BD ). However, the molecular and neuronal basis of BD , as well as the mechanisms of Li + actions are poorly understood. Cellular and biochemical studies identified G proteins as being among the cellular targets for Li + action, while genetic studies indicated an association with the KCNJ 3 gene, which encodes the G protein‐activated inwardly rectifying K + ( GIRK ) channels. GIRK channels regulate neuronal excitability by mediating the inhibitory effects of multiple neurotransmitters and contribute to the resting potassium conductance. Here, we explored the effects of therapeutic dose of Li + on neuronal excitability and the role of GIRK channels in Li + actions. Methods Effects of Li + on excitability were studied in hippocampal brain slices using whole‐cell electrophysiological recordings. Results A therapeutic dose of Li + (1 mM) dually regulated the function of GIRK channels in hippocampal slices. Li + hyperpolarized the resting membrane potential of hippocampal CA 1 pyramidal neurons and prolonged the latency to reach the action potential threshold and peak. These effects were abolished in the presence of tertiapin, a specific GIRK channel blocker, and at doses above the therapeutic window (2 mM). In contrast, Li + reduced GIRK channel opening induced by GABA B receptor (GABA B R) activation, causing reduced hyperpolarization of the membrane potential, attenuated reduction of input resistance, and a smaller decrease of neuronal firing. Conclusions A therapeutic dose of Li + reduces the span of GIRK channel‐mediated inhibition due to enhancement of basal GIRK currents and inhibition of GABA B R evoked responses, providing an important link between Li + action, neuronal excitability, and cellular and genetic targets of BD .