Pharmacological protection of synaptic function, spatial learning, and memory from transient hypoxia in rats.
Hypoxia significantly reduced cholinergic theta activity in rat CA1 field and intracellular theta in the CA1 pyramidal cells, recorded in hippocampal slices. The hypoxic responses of the hippocampal CA1 pyramidal cells to a brief hypoxia consisted of a short period of "synaptic arrest", observed as an elimination of excitatory postsynaptic current under voltage clamp and recovered immediately as oxygenation was reinitiated. The hypoxic synaptic arrest was not associated with reduced postsynaptic responses of the pyramidal cells to externally applied L-glutamate, suggesting that the synaptic arrest might result from a presynaptic mechanism. The hypoxic synaptic arrest was abolished in the presence of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a specific adenosine A(1) receptor antagonist. Blocking adenosine A(1) receptors also eliminated effects of hypoxia on the hippocampal CA1 field theta activity and intracellular theta of the CA1 pyramidal cells. In behaving rats, brief hypoxia impaired their water maze performance in both the escape latency and probe tests. The impairment was prevented by intralateral cerebroventricular injections of DPCPX. These results suggest that hypoxia releases adenosine and produces an inhibition of synaptic transmission and intracellular signal cascade(s) involved in generation/maintenance of hippocampal CA1 theta activity. This protection of synaptic efficacy and spatial learning through adenosine A(1) receptor antagonism may represent an effective therapeutic strategy to eliminate functional interruption due to transient hypoxic episodes and/or chronic hypoxia secondary to compromise of respiratory function.
Sun
Miao-Kun
MK
Blânchette Rockefeller Neurosciences Institute, Rockville, Maryland 20850, USA. mksun@brni-jhu.org
Xu
Hui
H
Alkon
Daniel L
DL
D000818:Animals; D004558:Electric Stimulation; D004594:Electrophysiology; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects; D002534:Hypoxia, Brain / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology*; D066298:In Vitro Techniques; D007858:Learning / Q000187:drug effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D009473:Neuronal Plasticity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010275:Parasympathetic Nervous System / Q000187:drug effects; D018408:Patch-Clamp Techniques; D058915:Purinergic P1 Receptor Antagonists; D017966:Pyramidal Cells / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013028:Space Perception / Q000187:drug effects*; D013569:Synapses / Q000187:drug effects* / Q000473:pathology
D018696:Neuroprotective Agents; D058915:Purinergic P1 Receptor Antagonists; D018698:Glutamic Acid