In the mature CNS, coincident pre- and postsynaptic activity decreases the strength of gamma-aminobutyric acid (GABA)(A)-mediated inhibition through a Ca2+-dependent decrease in the activity of the neuron-specific K+-Cl- cotransporter KCC2. In the present study we examined whether coincident pre- and postsynaptic activity can also modulate immature GABAergic synapses, where the Na+-K+-2Cl- (NKCC1) cotransporter maintains a relatively high level of intracellular chloride ([Cl-](i)). Dual perforated patch-clamp recordings were made from cultured hippocampal neurons prepared from embryonic Sprague-Dawley rats. These recordings were used to identify GABAergic synapses where the reversal potential for Cl- (ECl) was hyperpolarized with respect to the action potential threshold but depolarized with respect to the resting membrane potential. At these synapses, repetitive postsynaptic spiking within +/- 5 ms of GABAergic synaptic transmission resulted in a hyperpolarizing shift of ECl by 10.03 +/- 1.64 mV, increasing the strength of synaptic inhibition. Blocking the inward transport of Cl- by NKCC1 with bumetanide (10 microm) hyperpolarized ECl by 16.14 +/- 4.8 mV, and prevented this coincident activity-induced shift of ECl. The bumetanide-induced hyperpolarization of ECl occluded furosemide, a K+-Cl- cotransporter antagonist, from producing further shifts in ECl. Together, this indicates that brief coincident pre- and postsynaptic activity strengthens inhibition through a regulation of NKCC1. This study further demonstrates ionic plasticity as a mechanism underlying inhibitory synaptic plasticity.
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