EFFECT OF BICUCULLINE ON THALAMIC ACTIVITY - A DIRECT BLOCKADE OF I-AHP IN RETICULARIS NEURONS

The thalamic reticular nucleus (RTN) is the major source of inhibitory contacts in the thalamus and thus plays an important role in regulati ng the excitability of the thalamocortical network. Inhibition occurs through GABAergic synapses on relay cells as well as through GABAergic synapses between reticularis neurons themselves. Here we report that the role and mechanisms of this inhibition, which frequently have been studied using N-methyl derivatives of the gamma-aminobutyric acid-A ( GABA(A)) receptor antagonist bicuculline, should be revisited. Using t he whole cell patch-clamp technique in thalamic slices from young rats , we observed an enhancement by bicuculline methiodide, methobromide, and methochloride (collectively referred to as bicuculline-M; 5-60 mu M) of the low-threshold calcium spike burst in RTN neurons that persis ted-in the presence of tetrodotoxin (1 mu M) and was not reproduced in picrotoxin (100-300 mu M). The effect did not involve activation of a ny GABA receptor subtype. Voltage-clamp recordings showed that bicucul line-hl blocked the current underlying the low-threshold spike burst a fterhyperpolarization (AHP), an effect that was mimicked by apamin (10 0 nM). Recordings from nucleated patches extracted from reticularis ne urons demonstrated that this effect was not mediated by modulation of the release of an unidentified neurotransmitter but that bicuculline-M directly blocks small conductance (SK) channels. The AHP-blocking eff ect also was observed in other brain regions, demonstrating that altho ugh bicuculline-M is a potent GABA(A) receptor antagonist, it is of li mited value in assessing GABAergic network interactions, which should be studied using picrotoxin or bicuculline-free base. However, bicucul line-hl may provide a useful tool for developing nonpeptide antagonist s of SK channels.