The sodium pump (Na+/K+-ATPase) is nearly ubiquitous in cells and serves diverse functions related to maintenance of transmembrane Na+ and K+ gradients. Although its importance is often regarded mainly in relation to its homeostatic roles, the Na+ pump is actually a family of enzymes heterogeneously distributed in the brain and subject to regulation by many endogenous factors, suggesting the existence of a broad range of Na+ pump functions. This project seeks to test the general hypothesis that regulation of the Na+ pump provides an important mechanism for the control of neuronal excitability. Reversible, partial Na+ pump inhibition and stimulation will be used, in conjunction with electrophysiological techniques, in the rat hippocampal slice to study the mechanisms by which the Na+ pump affects excitability. The major focus is on epileptiform activity induced by partial Na pump inhibition.
Specific aims of the project will test the following hypotheses: 1. PPI causes epileptiform activity by selectively reducing synaptic inhibition. 2. Ion fluxes through synaptic channels can lead to Na pump activation. 3. PPI induces a persistent increase in excitability in CA3 through an LTP-like process. 4. PPI causes an LTD-like suppression of synaptic responses in CA1. 5. PPI suppresses burst discharge processes in slices from juvenile animals. Na+ pump dysfunction has been implicated in a number of disease states, including epilepsy, but the wealth of information on the molecular biology and biochemistry of the Na+ pump is not matched by a comparable understanding of its physiological roles. This proposal is a step towards filling the gap.
