Rapid decline of GABAA receptor subunit mRNA expression in hippocampus following transient cerebral ischemia in the gerbil.
Inhibitory neurotransmission may play an important role in neuronal degeneration following transient cerebral ischemia. We studied the effect of transient forebrain ischemia on the GABAA receptor system in the gerbil hippocampus. Gerbils were subjected to 5 minutes of bilateral carotid occlusion and were sacrificed at various times over 4 days following reperfusion. There was a substantial loss of pyramidal cells in the CA1 area of the hippocampus 4 days following ischemia. No cell loss was detected in CA3 pyramidal cells of the hippocampus, granule cell layer of the dentate gyrus, and ventroposterior medial and ventroposterior lateral nuclei of the thalamus at any time following ischemia. Examination of brain slices by in situ hybridization histochemistry revealed that a change in expression of the GABAA receptor alpha 1 and beta 2 subunit mRNAs occurred in two phases following onset of reperfusion. The early phase (rapid) occurred within the first 4 hours following reperfusion. The expression of mRNAs significantly decreased (up to 25%) within 1 hour after occlusion in CA1 and CA3 pyramidal cell layers of the hippocampus and in the granule cell layer of the dentate gyrus. The expression of the mRNAs in these regions continued to decrease for 4 hours (up to 43%). In the second phase, which began between 4 and 12 hours following reperfusion, mRNA expression started to return to control levels in CA3 hippocampus and in the dentate. However, expression of both mRNAs continued to decline slowly in the CA1 pyramidal cell layer (up to 85%) over the next 3 days, concomitantly with degeneration of the CA1 pyramidal cells. Expression of mRNAs in the ventroposterior medial or ventroposterior lateral nuclei of the thalamus was similar to control values. To determine if a change in GABAA receptor distribution paralleled changes in receptor subunit mRNA expression, we also measured the binding of [35S]t-butylbicyclophosphorothionate to GABAA receptor chloride channels. The t-butylbicyclophosphorothionate [35S] binding decreased between 1 and 4 days after reperfusion in the dendritic fields of CA1 pyramidal cells (strata oriens, radiatum, and lacunosum-moleculare) but not in the pyramidal cell body layer. These results indicate that expression of GABAA receptor subunit mRNAs decrease well before CA1 pyramidal cell degeneration and loss of GABAA receptors. At present, it is not clear if an early loss of mRNA expression after an ischemic insult leads to a functional defect in GABAA receptors. If so, a loss of GABA neurotransmission may contribute to the development of neuronal degeneration following cerebral ischemia.(ABSTRACT TRUNCATED AT 400 WORDS)
Li
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H
Department of Pharmacology, Duke University Medical Center, Durham, NC 27710.
Siegel
R E
RE
Schwartz
R D
RD
D000818:Animals; D002339:Carotid Arteries; D018118:Chloride Channels / Q000378:metabolism; D003250:Constriction; D005786:Gene Expression Regulation; D005849:Gerbillinae; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D017403:In Situ Hybridization; D015640:Ion Channel Gating; D002546:Ischemic Attack, Transient / Q000378:metabolism*; D008297:Male; D009410:Nerve Degeneration; D012333:RNA, Messenger / Q000096:biosynthesis*; D018079:Receptors, GABA / Q000096:biosynthesis* / Q000235:genetics; D015424:Reperfusion; D009435:Synaptic Transmission; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D018118:Chloride Channels; D012333:RNA, Messenger; D018079:Receptors, GABA; D005680:gamma-Aminobutyric Acid