Synchronous firing of inhibitory interneurons results in saturation of fast GABAA IPSC magnitude but not saturation of fast inhibitory efficacy in rat neocortical pyramidal cells

Abstract

The kinetic properties of evoked fast inhibitory postsynaptic currents were examined to elucidate factors underlying the limit on the magnitude of fast inhibition in neocortex. Using whole-cell voltage-clamp recordings from layer V pyramidal neurons in slices of rat somatosensory cortex, fast gamma-aminobutyric acid-A (GABA[A])ergic inhibitory postsynaptic currents were selectively recorded by holding cells at potentials equal to excitatory postsynaptic current reversal (approximately 0 mV). As stimulus intensity was increased, the magnitude and duration of the fast inhibitory postsynaptic current increased. Over the range of stimuli applied (2-10 V), fast GABA(A)-mediated inhibitory postsynaptic currents reached a maximum peak conductance of 25.9 +/- 4.2 nS (range 10.5-41.2 nS) at intensities approximately 2-times threshold. As stimulus intensities were increased beyond this point of maximal conductance, the time constant of current decay increased as function of stimulus strength, while rise time remained unaffected. Exposure to nominally magnesium-free solutions did not affect maximal peak conductances of fast inhibitory postsynaptic currents, but did cause an increase in the time constants of current decay by 66.3 +/- 23.6%, resulting in an 85.6 +/- 24.6% increase in the total charge flux carried by single inhibitory postsynaptic currents. This effect may be due to prolonged activation of postsynaptic GABA(A) receptors by excess GABA released in response to increased excitation. Exposure to the GABA uptake blocker, nipecotic acid, similarly prolonged current decay without affecting the maximal peak conductance. Our findings suggest that the limit on recruitment of evoked fast inhibition in neocortical layer V pyramidal cells arises from the saturation of postsynaptic GABA(A) receptors. However, while there is a limit to the peak fast inhibitory postsynaptic conductance which can be recruited with increasing excitation, inhibitory strength may still be modulated by increasing charge flux through the prolongation of fast inhibition.

GABA Transporter-1 (GAT1)-Deficient Mice: Differential Tonic Activation of GABAAVersus GABABReceptors in the Hippocampus

“…Previous electrophysiological studies showed that the decay of electrically evoked inhibitory postsynaptic currents and potentials are prolonged by GAT1 inhibition in hippocampal and neocortical brain slices (Engel et al 1998;Ling and Benardo 1998;Roepstorff and Lambert 1994;Thompson and Gähwiler 1992). On the other hand, the kinetics of mIPSCs, which reflect the quantal GABAergic transmission, are normally not shaped by GABA uptake (Isaacson et al 1993;.…”

A pharmacological examination of GABAb receptor-mediated inhibition in the amygdala of fast and slow kindling rat strains; in VIVO and in VITRO studies.

“…These findings are in agreement with other studies suggesting that inhibitory dendritic conductances are subjected to greater filtering than in or near the soma (Hausser, 2001). This in turn w ill lead to a prolongation o f IPSC rise and decay times than their proximal counterparts (Ling and Benardo, 1998). To this end, inhibition mediated by the slow GABAa conductance component appears to be more effective than the fast G ABAa component for regulating excitatory responses, especially of the N-methyl-D-aspartate (NMDA) type (Kapur etal., 1997).…”

Valproate Prevents Epileptiform Activity After Trauma in an In Vitro Model in Neocortical Slices

“…Most important, we found that sodium valproate enhanced monosynaptic fast IPSP strength, primarily through a prolongation of the IPSP decay time. This is similar to previous results from this laboratory (using a different recording methodology) on the effects of nipecotic acid, a GABA reuptake inhibitor (10). Although this mechanism is not one attributed to valproate, the inhibition of GABA transaminase is (18), and this could explain the increase in IPSP duration with valproate.…”