Distinct functional and pharmacological properties of tonic and quantal inhibitory postsynaptic currents mediated by gamma-aminobutyric acid(A) receptors in hippocampal neurons

gamma -Aminobutyric acid (GABA), the principal inhibitory neurotransmitter, activates a persistent low amplitude tonic current in several brain region s in addition to conventional synaptic currents. Here we demonstrate that G ABA(A) receptors mediating the tonic current in hippocampal neurons exhibit functional and pharmacological properties different from those of quantal synaptic currents. Patch-clamp techniques were used to characterize miniatu re inhibitory postsynaptic currents (mIPSCs) and the tonic GABAergic curren t recorded in CA1 pyramidal neurons in rat hippocampal slices and in dissoc iated neurons grown in culture. The competitive GABA(A) receptor antagonist s, bicuculline and picrotoxin, blocked both the mIPSCs and the tonic curren t. In contrast, mIPSCs but not the tonic current were inhibited by gabazine (SR-95531). Coapplication experiments and computer simulations revealed th at gabazine bound to the receptors responsible for the tonic current but di d not prevent channel activation. However, gabazine competitively inhibited bicuculline blockade. The unitary conductance of the GABA(A) receptors und erlying the tonic current (similar to6 pS) was less than the main conductan ce of channels activated during quantal synaptic transmission (similar to 1 5-30 pS). Furthermore, compounds that potentiate GABA(A) receptor function including the benzodiazepine, midazolam, and anesthetic, propofol, prolonge d the duration of mIPSCs and increased tonic current amplitude in cultured neurons to different extents. Clinically-relevant concentrations of midazol am and propofol caused a greater increase in tonic current compared with mI PSCs, as measured by total charge transfer. In summary, the receptors under lying the tonic current are functionally and pharmacologically distinct fro m quantally activated synaptic receptors and these receptors represent a no vel target for neurodepressive drugs.