Presynaptic factors in the regulation of DST expression in hippocampus

We studied the mechanisms by which GABA release is reduced in the retrograde signaling process called depolarization-induced suppression of inhibition (DSI). DSI is mediated by endocannabinoids in acute and cultured organotypic hippocampal slices. We examined a variety of K+ channel antagonists to determine the nature of the K+ channel that, when blocked, reduces DSI. Among 4-AP, TEA, dendrotoxin, Cs, margatoxin, and charybdotoxin, only 4-AP was highly effective in blocking DSI, suggesting that a K+ channel composed in part of K-V1.4, K-V1.5 or K-V1.7 subunits can readily regulate DSI. The inhibition of DSI by 4-AP is largely overcome by reducing [Ca2+](o), however, suggesting that DSI expression can be prevented by saturation of the release process when a K-V1.X channel is inhibited. DSI of agatoxin- and TTX-insensitive mIPSCs was unaffected by 4-AP, but was largely occluded by omega-conotoxin GVIA, indicating that block of presynaptic N-type Ca2+ channels is probably a major mechanism of DSI expression. Significant DSI of mIPSCs remained in omega-conotoxin, hence we infer that block of N-channels does not fully explain hippocampal DSI expression. (C) 2002 Elsevier Science Ltd. All rights reserved.