Retrograde signalling in depolarization-induced suppression of inhibition in rat hippocampal CA1 cells.

1. We have investigated the phenomenon of 'depolarization-induced suppression of inhibition' (DSI) using whole-cell voltage-clamp techniques in Ca1 pyramidal cells of rat hippocampal slices. DSI was induced by eliciting voltage-dependent calcium (Ca2+) currents with 1 s voltage steps of +60 to +90 mV from the holding potential. DSI was apparent as a reduction in synaptic GABAA responses for a period of about 1 min following the voltage step. 2. TTX-sensitive spontaneous IPSCs (sIPSCs) were susceptible to DSI, while TTX-resistant miniature inhibitory postsynaptic current (mIPSCs) were not. Miniature IPSCs are ordinarily infrequent and independent of external Ca2+ in the CA1 region. To increase the frequency of mIPSCs and to induce a population of Ca(2+)-sensitive mIPSCs, we increased the bath K+ concentration to 15 mM. The increased mIPSCs were also insensitive to DSI, however. 3. T whole-cell pipette-filling solution contained 5 mM 2(triethylamino-N-(2,6-dimethyl-phenyl)acetamide (QX-314) to block voltage-dependent Na+ currents and caesium to block K+ currents. Nevertheless, bath application of 50 microM 4-aminopyridine (4-AP) or 250 nM veratridine both clearly reduced DSI, evidently by acting at presynaptic sites. 4. The amplitudes of monosynaptically evoked IPSCs (elicited in the presence of 10 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 50 microM 2-amino-5-phosphonovaleric acid (APV)) were dramatically reduced during the DSI period. Weak stimulation produced small IPSCs and occasional 'failures' of transmission during the control period. The percentage of failures increased markedly during the DSI period. Moderate-intensity stimulation produced larger IPSCs that were often composed of distinguishable multiquantal components. All-or-none failures of multiquantal IPSC components also occurred during DSI. 5. The degree of paired-pulse IPSC depression did not change during DSI, whereas it was decreased, as expected, by baclofen. 6. We conclude that the data represent novel evidence that DSI is mediated by a retrograde signalling process possibly involving presynaptic axonal conduction block.