QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, March 2, 2005, 25(9):2376-2385; doi:10.1523/JNEUROSCI.4940-04.2005

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Maas, J. W. Articles by Muglia, L. J. Search for Related Content PubMed PubMed Citation Articles by Maas, J. W., Jr Articles by Muglia, L. J.

 Previous Article  |  Next Article 

Neurobiology of Disease
Calcium-Stimulated Adenylyl Cyclases Modulate Ethanol-Induced Neurodegeneration in the Neonatal Brain

James W. Maas, Jr,¹ Ricardo A. Indacochea,¹ Lisa M. Muglia,¹ Timothy T. Tran,¹ Sherri K. Vogt,¹ Tim West,² Ann Benz,³ Amanda A. Shute,³ David M. Holtzman,^2,4,5 Steven Mennerick,³ John W. Olney,³ and Louis J. Muglia^1,4

Departments of ¹Pediatrics, ²Neurology, ³Psychiatry, and ⁴Molecular Biology and Pharmacology and ⁵Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110

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.

Key words: adenylyl cyclase; calcium; cAMP; ethanol; knock-out mouse; pharmacology

---

Received Dec 3, 2004; revised January 15, 2005; accepted January 17, 2005.

This article has been cited by other articles:

				V. J. Watts Adenylyl Cyclase Isoforms as Novel Therapeutic Targets: An Exciting Example of Excitotoxicity Neuroprotection Mol. Interv., April 1, 2007; 7(2): 70 - 73. [Abstract] [Full Text] [PDF]

				H. Wang, B. Gong, K. I. Vadakkan, H. Toyoda, B.-K. Kaang, and M. Zhuo Genetic Evidence for Adenylyl Cyclase 1 as a Target for Preventing Neuronal Excitotoxicity Mediated by N-Methyl-D-aspartate Receptors J. Biol. Chem., January 12, 2007; 282(2): 1507 - 1517. [Abstract] [Full Text] [PDF]

				C. P. Chen, P. Kuhn, K. Chaturvedi, N. Boyadjieva, and D. K. Sarkar Ethanol Induces Apoptotic Death of Developing beta-Endorphin Neurons via Suppression of Cyclic Adenosine Monophosphate Production and Activation of Transforming Growth Factor-beta1-Linked Apoptotic Signaling Mol. Pharmacol., March 1, 2006; 69(3): 706 - 717. [Abstract] [Full Text] [PDF]

				A. E. Medina, T. E. Krahe, and A. S. Ramoa Restoration of Neuronal Plasticity by a Phosphodiesterase Type 1 Inhibitor in a Model of Fetal Alcohol Exposure J. Neurosci., January 18, 2006; 26(3): 1057 - 1060. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help