Excessive N-methyl-D-aspartate receptor (NMDAR) activation is thought to contribute to pathophysiology in a variety of neurological disorders. This involvement led to the development of NMDAR antagonists for therapeutic applications. High-affinity competitive and noncompetitive NMDAR antagonists proved unsuitable for human use due to prominent adverse effects. High-affinity, competitive antagonists also can promote synaptic reorganization and glutamate receptor up-regulation in experimental systems, which may lead to anomalous neuronal circuits and individual synapse abnormalities. Moderate-affinity noncompetitive and NR2B-selective NMDAR antagonists elicit fewer adverse effects and remain viable therapeutic options. Whether these antagonists alter neuronal circuits and individual synapses remains largely unexplored. NMDAR antagonists hold promise to prevent acquired epilepsy. Current therapies target seizures associated with fully developed epilepsy, but cannot prevent epilepsy acquired following brain insult. Epileptogenesis, the process by which a normal brain becomes prone to chronic seizures, is associated with circuitry rearrangements and individual synapse abnormalities. Thus, NMDAR antagonists that induce synaptic reorganization and alter individual synapses may exacerbate rather than inhibit epileptogenesis. Our goal for the proposed study is to document the effects of three distinct classes of NMDAR antagonists (NR2B-selective, high-affinity competitive and moderate-affinity uncompetitive) on epileptogenesis and to determine whether the effects of different classes of NMDAR antagonists on epileptogenesis are associated with alterations in synaptic plasticity.
These aims will be accomplished using a combination of pharmacological, electrophysiological, histological and histochemical approaches in a rat hippocampal slice culture model of epileptogenesis. Results from this study will provide new information about the benefits and potential drawbacks of chronic treatment with different classes of NMDAR antagonists. These data also will lead to a greater understanding of the role of synaptic plasticity in epileptogenesis. This information is crucial in providing a rational basis for development of therapies designed to prevent acquired epilepsy.
