Abstracts

RATIONALE:_We have previously shown in hippocampal slices that CA1 pyramidal cells and GABAergic interneurons express functional glycine-gated chloride channels (GlyRs). We are testing the hypothesis that activation of postsynaptic GlyRs will depress synaptic transmission. METHODS: To test the hypothesis, whole-cell recordings were obtained from CA1 pyramidal cells and stratum (s.) radiatum interneurons in rat hippocampal slices (P21-25)and synaptic transmission was electrically evoked via a stimulating electrode placed in CA1 s. radiatum. Agonists and antagonists were applied via bath perfusion or by pressure ejection. RESULTS:_We now report that 300 M glycine or 1mM taurine, a GlyR agonist, depresses AMPA (n=14)and GABAA(n=8)transmission recorded from both cell types by nearly 80%. This depression is antagonized by 1 M strychnine and correlates with a decrease in cell Rinput. AMPA and GABAA currents elicited by exogenous application of transmitter were similarly depressed by glycine (in the presence of 1 M TTX and 100 M d,l-APV), suggesting a probable postsynaptic mechanism. As further support of this idea, inclusion of 1mM DIDS (a chloride channel blocker)in the internal solution abolished the glycine-induced depression of synaptic and exogenously elicited AMPA and GABAA currents. Application of the glycine GlyT1 transport inhibitor, sarcosine (100 nM), caused a strychnine-sensitive reduction( 50%)of synaptic transmission (n=5), and effectively reduced a suprathreshold EPSP to a subthreshold event. These results indicate that GlyR activation can prevent an excitatory synaptic potential from propagating an action potential to the postsynaptic neuron. CONCLUSIONS: Our data suggests that when postsynaptic GlyRs are activated, the responding neuron will become synaptically isolated from the network. This mechanism may be beneficial during periods of high neuronal activity, as occurs during seizures, following which glycine levels are elevated. We propose that GlyRs may provide a new therapeutic target for the treatment of epileptic activity. Supported by the Epilepsy Foundation to LLM.