Calcium-stimulated adenylyl cyclases modulate ethanol-induced neurodegeneration in the neonatal brain.
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 GABA(A) 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.
Maas
James W
JW
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Indacochea
Ricardo A
RA
Muglia
Lisa M
LM
Tran
Timothy T
TT
Vogt
Sherri K
SK
West
Tim
T
Benz
Ann
A
Shute
Amanda A
AA
Holtzman
David M
DM
Mennerick
Steven
S
Olney
John W
JW
Muglia
Louis J
LJ
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000813:Anilides / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology; D002118:Calcium / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000431:Ethanol / Q000097:blood; D018757:GABA Modulators / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology; D017403:In Situ Hybridization / Q000379:methods; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D019636:Neurodegenerative Diseases / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009842:Oligopeptides / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D016622:Silver Staining / Q000379:methods; D013997:Time Factors
D000813:Anilides; D018757:GABA Modulators; D018696:Neuroprotective Agents; D009842:Oligopeptides; C475509:aspartyl-glutamyl-valyl-aspartyl-p-nitroanilide; D000431:Ethanol; D016291:Dizocilpine Maleate; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D000262:Adenylyl Cyclases; C106670:adenylyl cyclase 1; D002118:Calcium; D010634:Phenobarbital
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