Pharmacological isolation of the synaptic and nonsynaptic components of the GABA-mediated biphasic response in rat CA1 hippocampal pyramidal cells

High-frequency stimulation (HFS) applied to stratum radiatum of a rat hippo campal slice in the presence of ionotropic glutamate receptor antagonists e vokes a biphasic GABA(A) receptor-dependent response in CA1 pyramidal neuro ns, with a brief hyperpolarizing IPSP (hIPSP) followed by a long-lasting de polarization. We show now that it is possible to pharmacologically separate the hIPSP and late depolarization from one another. In neurons intracellul arly perfused for 1-2 hr with F- as the major anion and no ATP, the hIPSP ( and the corresponding current, hIPSC) evoked by HFS was blocked, whereas ne ither the late depolarization nor its underlying current was attenuated. In contrast, internal perfusion with a high concentration (5 mM) of the imper meant lidocaine derivative QX-314 selectively abolished the depolarizing co mponent of the biphasic response and also strongly reduced depolarizations evoked by extracellular microinjection of K+. Bath application of quinine ( 0.2-0.5 mM) or quinidine (0.1 mM) resulted in a pronounced inhibition of th e HFS-induced extracellular K+ concentration ([K+](o)) transient but not of the bicarbonate-dependent alkaline shift in extracellular pH. The attenuat ion of the [K+](o) transient was closely paralleled by a suppression of the HFS-evoked depolarization but not of the hIPSP. Quini(di)ne did not affect depolarizations induced by exogenous K+ either. These data provide direct pharmacological evidence for the view that the HF S-induced biphasic response of the pyramidal neuron is composed of mechanis tically distinct components: a direct GABA(A) receptor-mediated phase, whic h is followed by a slow, nonsynaptic [K+](o)-mediated depolarization. The b icarbonate-dependent, activity-induced [K+](o) transient can be blocked by quini(di)ne, whereas its depolarizing action in the pyramidal neuron is inh ibited by internal QX-314. The presence of fundamentally distinct component s in GABA(A) receptor-mediated actions evoked by HFS calls for further inve stigations of their functional role(s) in standard experimental maneuvers, such as those used in studies of synaptic plasticity and induction of gamma oscillations.