• Partial inhibition of sodium,potassium-ATPase activity modulates neuronal excitability in area CA1 of rat hippocampus

      Mason, Susanne Elizabeth; Alger, Bradley Eugene (2001)
      Because of its physiological role in maintaining cellular homeostasis, regulation of the Na+,K+-ATPase is an ideal candidate mechanism for modulating excitability. Cardiac glycosides, which are specific ligands of the Na+,K+-ATPase, induce epileptiform burst firing in rat hippocampus that resembles interictal burst potentials observed between epileptic seizures. We investigated a role for shifts in transmembrane ion gradients, intrinsic membrane properties of principal neurons, coupling of postsynaptic dendritic inputs and firing properties, and the balance between excitatory and inhibitory synaptic inputs in burst firing induced by bath application of the cardiac glycoside dihydroouabain (DHO) in area CA1 of in vitro rat hippocampus.;Simultaneous field potential and K+-ion sensitive microelectrode recordings established that epileptiform burst firing induced by DHO was temporally correlated with inhibition of the Na+,K+-ATPase, but independent of increases in resting [K+]o of <1 mM or changes in intrinsic membrane properties of pyramidal neurons. DHO did enhance the ability of a given EPSP to generate an action potential. This enhanced EPSP-spike (E-S) coupling was associated with a prolonged depolarizing potential, presumably due to activation or enhancement of dendritic conductances. Enhanced E-S coupling, but not activation of the prolonged depolarizing potential, was occluded by the GABAA receptor antagonist, picrotoxin. DHO caused partial global suppression of excitatory and inhibitory synaptic transmission. Therefore, we conclude that partial inhibition of Na+,K +-ATPase activity causes epileptiform burst firing by creating an imbalance between excitatory and inhibitory inputs, in which overall excitation predominates. Partial Na+,K+-ATPase inhibition also caused a long-term suppression of fEPSPs that was of a similar magnitude as that induced by a chemical LTD protocol. Like the conventional LTD process, the DHO-induced long-term suppression could reverse a previously induced state of long-term potentiation (LTP). Unlike conventional LTD, however, the reversal of LTP by DHO did not require activation of NMDA or metabotropic glutamate receptors, suggesting that DHO activates signaling pathways downstream of the receptors. Therefore, in addition to a short-term effect on neuronal excitability, partial inhibition of Na+,K+-ATPase activity also mediates long-term synaptic plasticity in rat hippocampus.