| Abstract No.: | 210 |
| Country: | Canada |
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| Title: | Spike-Timing Dependent Plasticity of GABAergic Synapses in the Hippocampus |
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| Authors/Affiliations: | Melanie Woodin
University of Toronto, Department of Cell & Systems Biology, ON, Canada |
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| Content: | GABA (γ-aminobutyric acid) is the main inhibitory neurotransmitter in the mature CNS, and is found at one-third of all synapses in the brain. The GABAA receptor is the primary target of neuropharmacological drugs used in the treatment of sleep disturbances, anxiety disorders, restlessness, muscle tension, status epilepticus and as co-medication in anesthesia. It is also a primary target of internally released neurosteroids, which upon allosteric modulation of the GABAAR produce behavioural effects that include anxiolysis, sedation and analgesia. Neuropharmacological drugs and neurosteroids act by binding to the GABAA receptor and regulating its conductance. However, because the GABAAR is a Cl--permeable ion channel, the function of GABA is also determined by the regulation of neuronal Cl-. Recently, the importance of Cl- regulation in mediating GABAergic transmission has been demonstrated in numerous regions of the nervous system, with significant impacts of neuronal circuit functioning and clinical outcomes. We previously demonstrated in the mature central nervous system, that coincident pre- and postsynaptic activity decreases the strength of GABAA-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. 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. |
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