Persistent block of CA1 synaptic function by prolonged hypoxia

• Published in: Neuroscience 1999-05, Vol.90 (3), p.759-770
• Main Authors: Zhu, P.J., Krnjević, K.
• Format: Article
• Language: English
• Subjects: Afferent Pathways - physiopathology; Animals; APV; Biological and medical sciences; Central nervous system; Chronic Disease; depolarization; Electrophysiology; Fundamental and applied biological sciences. Psychology; glucose; Glucose - administration & dosage; Glucose - pharmacology; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - physiopathology; hyperpolarization; Hypoxia - physiopathology; In Vitro Techniques; Male; Osmolar Concentration; Rats; Rats, Sprague-Dawley; Receptors, Glutamate - classification; Receptors, Glutamate - physiology; Sodium Channels - physiology; Synapses - drug effects; Synapses - physiology; Synaptic Transmission - drug effects; Synaptic Transmission - physiology; transient recovery; TTX; Vertebrates: nervous system and sense organs
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/S0306-4522(98)00495-3

The effects of prolonged hypoxia were studied by field and intracellular recordings from hippocampal slices of the rat, kept submerged at 34°C. When artificial cerebrospinal fluid contained 10 mM glucose, even very long exposures to hypoxia or 300 μM cyanide (21–25 min) did not block field excitatory postsynaptic potentials and population spikes irreversibly. By contrast, in the presence of 4 mM glucose, hypoxia lasting only 9–13 min—ending 2–3 min after the characteristic transient recovery (“hypoxic injury potential”)—resulted in irreversible block of synaptic responses. Voltage-dependent sodium channels and N-methyl- d-aspartate receptors are involved, because irreversible block was prevented by tetrodotoxin (0.5 μM), kynurenate (2 mM) or dl-aminophosphonovalerate (50 μM), whereas 6,7-dinitroquinoxaline-2,3-dione (25 μM) suppressed only the transient recovery. The hypoxic suppression of afferent volleys in slices kept in 4 mM glucose was also prevented by kynurenate or aminophosphonovalerate. Intracellular recordings revealed opposite effects of hypoxia according to glucose concentration: in 10 mM glucose, mainly hyperpolarization; in 4 mM glucose, after a brief hyperpolarization, a major and usually irreversible depolarization. In the presence of kynurenate or tetrodotoxin, major depolarizations also occurred, but they were reversible. Thus, large depolarizations of hippocampal neurons do not necessarily lead to irreversible block of synaptic transmission: there is lasting damage only when hypoxia is combined with low glucose, presumably because a reduced supply of glycolytically generated ATP limits the Na +/K + pump's ability to maintain or restore membrane potentials and thus prevent excessive activation of N-methyl- d-aspartate receptors.