RAPID COMMUNICATION Endogenous GABA Activates Small-Conductance K Channels Underlying Slow IPSCs in Rat Hippocampal Neurons

De Koninck, Yves and Istvan Mody. Endogenous GABA actition of these receptors to raise the intracellular concentration vates small-conductance K channels underlying slow IPSCs in of G proteins to the level required for activation of the K rat hippocampal neurons. J. Neurophysiol. 77: 2202–2208, 1997. channels (Destexhe and Sejnowski 1995), or 3) cause the The objective of this study was to determine the properties of release of another neurotransmitter or cofactor necessary for K channels activated by endogenously released trasmitter under the activation of these receptors (Mody et al. 1994). To synaptic conditions. First, the levels of g-aminobutyric acid determine the relative contribution of endogenous GABA (GABA) were depleted in hippocampal nerve endings to establish versus that of other possible endogenous agents, we studied the relative contribution of endogenously released GABA to the the effects of depleting the releasable pool of GABA from activation of GABAB receptors mediating slow inhibitory postsyninterneuron terminals. This was accomplished by inhibiting aptic currents (IPSCs). Inhibition of glutamic acid decarboxylase and GABA reuptake effectively depleted ú85% of the releasable the GABA synthesizing enzyme glutamic acid decarboxylGABA pool, producing parallel reductions of GABAA and GABAB ase (GAD) with isonicotinic acid hydrazide (isoniazid, receptor-mediated IPSCs, indicating that both classes of receptors INH) in combination with a reuptake blocker, nipecotic acid are activated synaptically by endogenously released GABA. Whole (NIP) (Geddes and Wood 1984; Maynert and Kaji 1962; cell patch-clamp recordings of stimulus-evoked slow IPSCs at poWood and Abrahams 1971; Wood et al. 1988). tentials hyperpolarized from the potassium reversal potential were To date, little is known about the properties of the K consistent with the activation of a nonrectifying (n Å 3) or slightly channels activated by endogenously released GABA, i.e., outwardly rectifying (n Å 4) K conductance by the endogenously under synaptic conditions. The GABAB receptors activated released GABA. Spectral analysis of the decay phase of GABAB by their endogenous agonist may engage channels distinct IPSCs revealed several time constants indicating complex underlyfrom those activated by synthetic GABAB agonists such as ing channel kinetics. Nonstationary variance analysis yielded a small unitary conductance in the range of 5–13 pS, consistent with baclofen or may favor distinct conductance or kinetic states a large number of channels activated during evoked currents. These for the same channel (for review, see Misgeld et al. 1995). results indicate that in granule cells of the dentate gyrus, GABA Our previous findings on synaptically elicited GABAB IPSCs released synaptically from interneuron terminals activates an unhave shown the activation of an outwardly rectifying K usually small K conductance, with no or slight outward rectificachannel (Otis et al. 1993), in contrast to inwardly rectifying tion. This conductance is therefore unlike those typically reported conductances activated by exogenous agonists (Misgeld et for neuronal G protein-coupled K channels or those activated al. 1995). Therefore, to determine the unitary conductance by exogenously applied baclofen with larger, inwardly rectifying of the K channels linked to GABAB receptors during their conductances. synaptic activation, we used nonstationary fluctuation analy-