Calcium-stimulated adenylyl cyclases modulate ethanol-induced neurodegeneration in the neonatal brain

James W. Maas, Ricardo A. Indacochea, Lisa M. Muglia, Timothy T. Tran, Sherri K. Vogt, Tim West, Ann Benz, Amanda A. Shute, David M. Holtzman, Steven Mennerick, John W. Olney, Louis J. Muglia

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Fetal alcohol exposure results in cognitive and neurobehavioral deficits, but the effects of modifying genetic loci on the severity of these sequelas have not been well characterized. Although the cAMP signaling pathway has been shown to be an important modulator of ethanol sensitivity in adult mice, its potential role in modulating ethanol-induced neurodegeneration has not been examined. Adenylyl cyclases (ACs) 1 and 8 produce cAMP in response to intracellular calcium elevation and modulate several aspects of neuronal function, including ethanol sensitivity. AC1 and AC8 are expressed widely throughout the brain of neonatal mice, and genetic deletion of both AC1 and AC8 in double-knock-out (DKO) mice enhances ethanol-induced neurodegeneration in the brains of neonatal mice. In addition, ethanol treatment induces significantly greater levels of caspase-3 activation in the brains of DKO mice compared with wild-type (WT) mice, reflecting higher numbers of apoptotic neurons. Administration of the NMDA receptor antagonist MK801 [(+)-5-methyl-10,11- dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine hydrogen maleate] or the GABAA receptor potentiator phenobarbital, which mimics components of the effects of ethanol on neurons, results in significantly greater neurodegeneration in the brains of neonatal DKO mice than WT mice. Furthermore, loss of a single calcium-stimulated AC isoform potentiates neurodegeneration after administration of ethanol, MK801, or phenobarbital. In contrast, the levels of physiological cell death, death after hypoxia/ischemia, and excitotoxic cell death are not increased in the brains of DKO mice. Thus, AC1 and AC8 are critical modulators of neurodegeneration induced by activity blockade in the neonatal brain and represent genetic loci that may potentially modify the severity of fetal alcohol syndrome.

Original languageEnglish
Pages (from-to)2376-2385
Number of pages10
JournalJournal of Neuroscience
Volume25
Issue number9
DOIs
StatePublished - Mar 2 2005

Keywords

  • Adenylyl cyclase
  • Calcium
  • Ethanol
  • Knock-out mouse
  • Pharmacology
  • cAMP

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