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.
|Reich, Christian G; Mason, Susanne E; Alger, Bradley E (2004) Novel form of LTD induced by transient, partial inhibition of the Na,K-pump in rat hippocampal CA1 cells. J Neurophysiol 91:239-47|
|Carlson, Gregory; Wang, Yue; Alger, Bradley E (2002) Endocannabinoids facilitate the induction of LTP in the hippocampus. Nat Neurosci 5:723-4|
|Varma, Namita; Brager, Darrin; Morishita, Wade et al. (2002) Presynaptic factors in the regulation of DSI expression in hippocampus. Neuropharmacology 43:550-62|
|Vaillend, Cyrille; Mason, Susanne E; Cuttle, Matthew F et al. (2002) Mechanisms of neuronal hyperexcitability caused by partial inhibition of Na+-K+-ATPases in the rat CA1 hippocampal region. J Neurophysiol 88:2963-78|
|Varma, N; Carlson, G C; Ledent, C et al. (2001) Metabotropic glutamate receptors drive the endocannabinoid system in hippocampus. J Neurosci 21:RC188|
|Kim, J; Alger, B E (2001) Random response fluctuations lead to spurious paired-pulse facilitation. J Neurosci 21:9608-18|
|Martin, L A; Wei, D S; Alger, B E (2001) Heterogeneous susceptibility of GABA(A) receptor-mediated IPSCs to depolarization-induced suppression of inhibition in rat hippocampus. J Physiol 532:685-700|