Glycine Channels and Hippocampal Excitability

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An inhibitory role of strychnine-sensitive glycine-gated chloride channels (GlyRs) in the brain has largely been ignored, despite the known expression of these receptors throughout the CNS. Interestingly, in some animal models of epilepsy, increasing the glycine levels in cerebral spinal fluid (CSF) depresses repetitive neuronal firing in hippocampus and cortex, implicated an important function of GlyRs in modulating neuronal excitability. GlyRs are expressed in hippocampus, a brain region highly dependent upon effective neuronal inhibition for normal function, however, the physiological role of these receptors is simply not known. The major hypothesis of this proposal is that in hippocampus, activation of GlyRs provides an undescribed, fundamental inhibitory mechanism that depresses the activity of excitatory pyramidal cells and inhibitory interneurons via direct activation of post-synaptic receptors and furthermore, that GlyR activation limits the of the neuronal network by depressing synaptic transmission. The long-term goal of this proposal is to establish a new role for GlyRs in hippocampus and to understand the cellular mechanisms mediating the effects of GlyR activation on neuronal activity. Extracellular popspike recordings of pyramidal cells and whole-cell and perforated patch recordings of pyramidal cells and interneurons in rat hippocampal slices will be combined with pharmacological tools to examined the functional expression of post- synaptic GlyRs in hippocampus throughout development and determine how activation of these receptors affects the synaptic network. We will carefully address the following Specific Aims: 1) To test the hypothesis that functional GlyR expression by pyramidal cells and interneurons continues throughout development and that the physiological and pharmacological properties of GlyRs expressed by these two cell types are the same and 2) To test the hypothesis that GlyR activation limits the activity of the synaptic network under basal and hyperexcitable conditions through a post-synaptically-mediated depression of transmission. The use of the hippocampal slice preparation in this study has the advantage of allowing direct glycine effects on individual neurons and synaptic circuits to be examined in a well-characterized system, where recorded neurons remain in their native synaptic environment. Our approach is anticipated to yield novel information that will pave the way for a new area of investigation into the inhibitory role of GlyRs. Furthermore, it is expected that the results from this study will provide insight into the design of novel therapeutic strategies for the prevention of seizure activity.