VOLTAGE-DEPENDENT DEACTIVATION AND DESENSITIZATION OF GABA RESPONSES IN CULTURED MURINE CEREBELLAR GRANULE CELLS

1. Electrophysiological recordings of GABAergic IPSCs and responses to applications of exogenous GABA were made from cultured murine cerebel lar granule cells. In both the presence and absence of tetrodotoxin, d epolarization of the postsynaptic cell. consistently produced a broade ning of the IPSC. This voltage-dependent change in kinetics arose enti rely from a slowing of the rate of current decay. The duration of mini ature IPSCs was increased by a significant but lesser amount by the GA BA uptake inhibitor nipecotic acid (300 mu m). 2. Five millisecond app lications of 1 mM GABA elicited rapidly activating, biexponentially de activating currents in patches derived from granule cell bodies. Deact ivation of these responses was slowed by membrane depolarization. This effect arose from an increased fractional participation of the slow c omponent of deactivation. The benzodiazepine flunitrazepam (1 mu M) sl owed deactivation at a holding potential of -70 mV but not at +50 mV. 3. Longer-lasting applications of GABA produced substantial biexponent ial macroscopic desensitization. The rate of desensitization was faste r at a holding potential of +50 mV than at -70 mV. The speeding of des ensitization at depolarized membrane potentials arose from an increase in the fractional contribution of the fast component of desensitizati on. 4. When two 5 ms, 1 mM GABA applications were made at an interstim ulus latency of 150 ms, the second response was consistently smaller t han the first. The depression of the second response was significantly heightened when the membrane potential was depolarized from -70 to +5 0 mV. 5. The degree of desensitization produced was closely linked to receptor occupancy. The rate of current deactivation was also voltage dependent when non-saturating, and therefore less desensitizing, appli cations of GABA were analysed. In contrast, both the GABA EC50 (simila r to 30 mu M) and the current activation kinetics at near EC50 agonist concentrations appeared to be voltage independent.