Development of GABA(A) receptor-mediated inhibitory postsynaptic currents in hippocampus

Abstract

Hippocampal CA1 pyramidal cells receive two kinetic classes of GABA(A) receptor-mediated inhibition: slow dendritic inhibitory postsynaptic currents (GABA(A,slow) IPSCs) and fast perisomatic (GABA(A,fast)) IPSCs. These two classes of IPSCs are likely generated by two distinct groups of interneurons, and we have previously shown that the kinetics of the IPSCs have important functional consequences for generating synchronous firing patterns. Here, we studied developmental changes in the properties of GABA(A,fast) and GABA(A,slow) spontaneous, miniature, and evoked IPSCs (sIPSCs, mIPSCs, and eIPSCs, respectively) using whole cell voltage-clamp recordings in brain slices from animals aged P10-P35. We found that the rate of GABA(A,slow) sIPSCs increased by over 70-fold between P11 and P35 (from 0.0017 to 0.12 s(-1)). Over this same age range, we observed a >3.5-fold increase in the maximal amplitude of GABA(A,slow) eIPSCs evoked by stratum lacunosum-moleculare (SL-M) stimuli. However, the rate and amplitude of GABA(A,slow) mIPSCs remained unchanged between P10 and P30, suggesting that the properties of GABA(A,slow) synapses remained stable over this age range, and that the increase in sIPSC rate and in eIPSC amplitude was due to increased excitability or excitation of GABA(A,slow) interneurons. This hypothesis was tested using bath application of norepinephrine (NE), which we found at low concentrations (1 microM) selectively increased the rate of GABA(A,slow) sIPSCs while leaving GABA(A,fast) sIPSCs unchanged. This effect was observed in animals as young as P13 and was blocked by coapplication of tetrodotoxin, suggesting that NE was acting to increase the spontaneous firing rate of GABA(A,slow) interneurons and consistent with our hypothesis that developmental changes in GABA(A,slow) IPSCs are due to changes in presynaptic excitability. In contrast to the changes we observed in GABA(A,slow) IPSCs, the properties of GABA(A,fast) sIPSCs remained largely constant between P11 and P35, whereas the rate, amplitude, and kinetics of GABA(A,fast) mIPSCs showed significant changes between P10 and P30, suggesting counterbalancing changes in action potential-dependent GABA(A,fast) sIPSCs. These observations suggest differential developmental regulation of the firing properties of GABA(A,fast) and GABA(A,slow) interneurons in CA1 between P10 and P35.