Abstracts

Rationale: GABA-A receptor properties at postsynaptic and extrasynaptic sites are characterized by inhibitory postsynaptic currents (IPSCs) and inhibitory tonic currents, respectively. The subunit composition of the GABA-A receptors determines the binding properties and receptor kinetic parameters for channel opening and desensitization, with dramatic effects on the response to GABA and other pharmalogical agents. A quantitative representation for the kinetic properties of GABA-A receptors reveals how ligand and drug exposure conditions determine receptor behavior and function, determines the circumstances that lead to a pathological loss of synaptic inhibition, and guides pharmacological manipulations that restore inhibition. Methods: A receptor-kinetic model for GABA-A receptors at synaptic and extrasynaptic sites in dentate gyrus granule cells has been optimized to fit experimentally measured IPSCs as well as evoked paired-pulse and tonic current responses after ligand and drug exposure. Results: Synaptic GABA-A receptors exposed to micromolar levels (3 microM) of GABA show rapid desensitization/downregulation with mIPSC amplitude reduction from -51.3 +/- 15.2 pA to -28.8 +/- 6.7 (p<.001). To explore if hi-frequency pulsatile release of GABA (as might occur with ‘fast ripples’) could also degrade synaptic inhibition, simulated stimulation of synaptic GABA-A receptors with frequencies of 20, 40 and 160 Hz for 400 msec duration reduces IPSC amplitudes by 39%, 57% and 75%, respectively. Furthermore, recovery from desensitization is slow and may be completely prevented by persistent intermittent discharges with frequencies as low as 0.5 to 2 Hz. Conclusions: Brief pulsatile ligand exposure can be equally as effective at inducing receptor desensitization and a loss of paired-pulse inhibition as tonic ligand exposure, and pulsatile and tonic effects can be additive. These results suggest that very brief hi-frequency discharges can lead to sustained loss of synaptic inhibition, especially if low-frequency interictal discharges also are present. Since loss of synaptic inhibition > 30% increases seizure likelihood, evoked GABA release with rapid desensitization of postsynaptic GABA-A receptors may be important in the transition from interictal to ictal states. In addition, model fits of phasic, tonic and evoked responses after drug exposure provide useful tools to quantify and optimize the specific effects of single and combination agents on kinetic rate constants, with more precise control of receptor behavior.