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Keywords:

  • cation-chloride cotransporter;
  • GABA;
  • inhibitory synaptic plasticity;
  • inhibitory synaptic transmission;
  • Sprague–Dawley

Abstract

In the mature CNS, coincident pre- and postsynaptic activity decreases the strength of γ-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 µm) 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.