title: Mechanisms of neuronal hyperexcitability caused by partial inhibition of Na+-K+-ATPases in the rat CA1 hippocampal region.
abstract: Extra- and intracellular records were made from rat acute hippocampal slices to examine the effects of partial inhibition of Na(+)-K(+)-ATPases (Na(+)-K(+) pumps) on neuronal hyperexcitability. Bath application of the low-affinity cardiac glycoside, dihydroouabain (DHO), reversibly induced interictal-like epileptiform bursting activity in the CA1 region. Burst-firing was correlated with inhibition of the pumps, which was assayed by changes in [K(+)](o) uptake rates measured with K(+)-ion-sensitive microelectrodes. Large increases in resting [K(+)](o) did not occur. DHO induced a transient depolarization (5-6 mV) followed by a long-lasting hyperpolarization (approximately 6 mV) in CA1 pyramidal neurons, which was accompanied by a 30% decrease in resting input resistance. Block of an electrogenic pump current could explain the depolarization but not the hyperpolarization of the membrane. Increasing [K(+)](o) from 3 to 5.5 mM minimized these transient shifts in passive membrane properties without preventing DHO-induced hyperexcitability. DHO decreased synaptic transmission, but increased the coupling between excitatory postsynaptic potentials and spike firing (E-S coupling). Monosynaptic inhibitory postsynaptic potential (IPSP) amplitudes declined to approximately 25% of control at the peak of bursting activity; however, miniature TTX-resistant inhibitory postsynaptic current amplitudes were unaffected. DHO also reduced the initial slope of the intracellular excitatory postsynaptic potential (EPSP) to approximately 40% of control. The conductances of pharmacologically isolated IPSPs and EPSPs in high-Ca/high-Mg-containing saline were also reduced by DHO by approximately 50%. The extracellular fiber volley amplitude was reduced by 15-20%, suggesting that the decrease in neurotransmission was partly due to a reduction in presynaptic fiber excitability. DHO enhanced a late depolarizing potential that was superimposed on the EPSP and could obscure it. This potential was not blocked by antagonists of NMDA receptors, and blockade of NMDA, mGlu, or GABA(A) receptors did not affect burst firing. The late depolarizing component enabled the pyramidal cells to reach spike threshold without changing the actual voltage threshold for firing. We conclude that reduced GABAergic potentials and enhanced E-S coupling are the primary mechanisms underlying the hyperexcitability associated with impaired Na(+)-K(+) pump activity.
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Vaillend
authors.forename: Susanne E
authors.initials: SE
authors.lastname: Mason
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Cuttle
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Alger
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D004056:Differential Threshold / Q000187:drug effects; D004594:Electrophysiology; D004827:Epilepsy / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005971:Glutamates / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D009474:Neurons / Q000502:physiology*; D009994:Osmolar Concentration; D010042:Ouabain / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D017729:Presynaptic Terminals / Q000502:physiology; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012146:Rest; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D009435:Synaptic Transmission / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D005971:Glutamates; C000977:dihydroouabain; D005680:gamma-Aminobutyric Acid; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase; D011188:Potassium