α5GABAA receptors regulate hippocampal sharp wave-ripple activity in vitro

Sharp waves and ripples (SWRs) are a basic endogenous network activity of the hippocampus. Growing evidence from in vivo studies suggests that this activity plays a crucial role in the process of memory consolidation. Generation of SWR activity requires an intricate interaction between pyramidal cells and specific classes of GABAergic interneurons. Though GABA(A)R-mediated transmission is required for generation of SWRs little is known about the possible implication of different subtypes of GABA(A)R in SWRs. One of the most abundant subtypes of GABA(A) receptor in the hippocampus contains the α5 subunit. This subtype is specifically located on pyramidal cells preferably mediating tonic inhibition and is implicated in memory processes. Using hippocampal slices of adult rats we investigated the effects of etomidate and L-655,708, two substances that display opposite effects on the α5 subunit-containing GABA(A) receptor (α5GABA(A)R), in the generation of spontaneous SWRs. We found that the two drugs at concentrations assumed to display preferential interaction with the α5GABA(A)Rs had opposite effects on: a) the probability of generation of SWRs in episodes of multiple consecutive events (i.e. clusters), b) the timing of generation of consecutive events in clusters, c) the strength of ripple oscillation and d) the ability of the network to initiate episodes of SWRs. Most of the opposite drug effects on SWRs were also observed at higher concentrations. The present finding demonstrates a crucial involvement of the α5GABA(A)Rs in the SWR activity suggesting that distinct facets of the GABA(A)R-mediated transmission are implicated in particular features of the SWRs activity. In addition, the present results are consistent with the known opposite effects of the two drugs on memory performance.