On the mechanisms underlying hypoxia-induced membrane depolarization in striatal neurons.
Clinical and experimental evidence has shown that the striatal neurons are particularly vulnerable to hypoxia and ischaemia. An excessive excitatory action of glutamate, released by the corticostriatal terminals, has been implicated in this peculiar vulnerability of striatal neurons. We have studied the effects of hypoxia on the membrane properties of striatal neurons intracellularly recorded from a corticostriatal slice preparation. Brief (2-10 min) periods of hypoxia produced reversible membrane depolarizations. During the initial phase of the hypoxia-induced depolarization the frequency of action potential discharge was transiently increased; 2-3 min after the onset of hypoxia the firing activity was fully abolished. Brief periods of hypoxia also caused a reversible reduction of the amplitude of the excitatory postsynaptic potentials (EPSPs) evoked by cortical stimulation. Longer period of hypoxia (12-20 min) produced irreversible membrane depolarizations. In voltage-clamp experiments hypoxia caused an inward current coupled with an increased membrane conductance. Tetrodotoxin (TTX) or low calcium (Ca2+)-high magnesium containing solutions blocked synaptic transmission, but they did not reduce the hypoxia-induced electrical changes. Antagonists of excitatory amino acid receptors failed to affect the electrical effects caused by oxygen deprivation. Hypoxia-induced inward currents were reduced either by the potassium (K+) channel blockers, barium and tetraethyl ammonium (TEA) cations, or by lowering external sodium (Na+) concentration. Blockade of ATP-dependent Na(+)-K+ pump by both ouabain and strophanthidin enhanced hypoxia-induced membrane depolarization/inward current. Our findings indicate that the release of excitatory amino acids does not seem to be required for the acute hypoxia-induced electrical changes in striatal neurons. Moreover, TTX-resistant Na+ influx and K+ currents seem to play an important role in the generation of hypoxia-induced electrical changes. These data also suggest that the selective vulnerability of striatal neurons to oxygen deprivation may be caused by their peculiar sensitivity to energy metabolism failure.
Calabresi
P
P
Clinica Neurologica, Università di Roma Tor Vergata, Italy.
Pisani
A
A
Mercuri
N B
NB
Bernardi
G
G
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism* / Q000503:physiopathology*; D004553:Electric Conductivity; D018846:Excitatory Amino Acids / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D002534:Hypoxia, Brain / Q000378:metabolism* / Q000503:physiopathology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects / Q000378:metabolism; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
D018846:Excitatory Amino Acids; D013757:Tetraethylammonium Compounds; D018698:Glutamic Acid; D013779:Tetrodotoxin; D019789:Tetraethylammonium; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium