The objective of this project is to define the role of excitatory and inhibitory amino acid neurotransmission in specific brainstem nuclei for the control of seizure susceptibility. In particular, nuclei that receive, process, and relay visceral inputs will be the focus of the proposed studies; these nuclei are the nucleus of the solitary tract (NTS) in the medulla, and the parabrachial nucleus (PBN) in the pons. Interest in the seizure-regulating potential of this circuitry has been prompted by the effectiveness of afferent vagal nerve stimulation for the control of intractable epilepsy, as well as in experimental seizure models. Preliminary results indicate that inhibition of the NTS and PBN in the rat, through glutamate blockade or GABA enhancement, confers protection against experimental seizures. These intriguing initial findings will be extended by investigating the pharmacological, neuroanatomical, and functional specificity of NTS and PBN influences on seizure control in a model of focally-evoked partial seizures. To accomplish the objective of this project, two Specific Aims are proposed to test two hypotheses: 1) that changes in glutamate and GABA transmission within subregions of NTS will exert site-specific effects on seizure susceptibility, 2) the anticonvulsant actions evoked by inhibition in NTS are mediated via synaptic connections with specific subregions in PBN. These hypotheses will be investigated through the focal application of specific agonists and antagonists of GABA receptors and glutamate receptor subtypes in subregions of the NTS and PBN. Alterations in seizure severity will be monitored via behavioral and in vivo physiological techniques. The data generated will provide insights into mechanisms via which autonomic and visceral inputs may regulate seizure susceptibility and epileptogenesis. This information will provide directions for novel therapeutic approaches to the treatment of epilepsy.
