Dynamism of GABA(A) receptor activation shapes the "personality" of inhibitory synapses

The kinetics of synaptic currents is largely determined by the postsynaptic receptor gating and the concentration time course of synaptic neurotransmitter. While the analysis of current responses to rapid agonist application provides the means to study the ligand-gated receptor gating, no direct tools are available to measure the neurotransmitter transient at GABAergic and glutamatergic synapses. Several lines of evidence indicate that the synaptic agonist transient is very brief suggesting that the activation of postsynaptic receptors occurs in conditions of extreme non-equilibrium. Such a dynamic pattern of activation has a crucial impact not only on the kinetics of synaptic currents but also on their susceptibility to pharmacological modulation. Thus, changes in the synaptic agonist waveform due to, for example modulation of the release machinery or uptake system may considerably alter both kinetics and pharmacology of synaptic currents. The use of modifiers of GABA(A) receptor gating and low-affinity antagonists provides a tool to estimate the time course of the agonist transient revealing that synaptic neurotransmitter is not saturating and that the agonist clearance occurs at a sub-millisecond time scale. It is proposed that dynamic conditions of synaptic receptor activation assure a broad spectrum of performance rendering the synapse extremely susceptible to a variety of modulatory processes.