Li + enhances GABAergic inputs to granule cells in the rat hippocampal dentate gyrus

Abstract

Defects in GABAergic interneurons are thought to be involved in the pathophysiology of bipolar disorder, and Li + has been used as a primary therapeutic agent in the treatment. We used the patch clamp technique to investigate whether Li + affects on spontaneous GABAergic synaptic inputs to granule cells (GCs) in hippocampal dentate gyrus. Extracellularly applied Li + (25 mM) markedly increased the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs), an effect completely blocked by picrotoxin or bicuculline. Li + increased sIPSCs frequency in the presence of tetrodotoxin (TTX), but to a lesser extent than its absence. Li + caused no change in the cumulative amplitude distribution of miniature IPSCs, indicating that a presynaptic mechanism is involved. When TTX was added in the presence of Li +, large-amplitude sIPSCs (>30 pA) were abolished specifically with no effect on small-amplitude sIPSCs (<20 pA). Intracellular Li + (6 mM) applied via the patch pipette depolarized the resting membrane potential in fast-spiking interneurons, resulting in an increase in spontaneous action potential (AP) firing. This change, however, was not observed in GCs. These results suggest that Li +-induced spontaneous AP firing in GABAergic interneurons contributes to the increase in GABAergic synaptic inputs to GCs.