Prenatal alcohol exposure alters GABAAα5 expression: A mechanism of alcohol-induced learning dysfunction

Toso, Laura; Roberson, Robin; Woodard, Jade; Abebe, Daniel; Spong, Catherine Y.

doi:10.1016/j.ajog.2006.01.098

« Previous Next »American Journal of Obstetrics & Gynecology
Volume 195, Issue 2 , Pages 522-527, August 2006

Prenatal alcohol exposure alters GABA_Aα₅ expression: A mechanism of alcohol-induced learning dysfunction

Laura Toso, MD
- Unit on Perinatal and Developmental Neurobiology, National Institute of Child and Human Development
- National Institue of Alcohol Abuse and Alcoholism, National Institute of Health, Bethesda, MD
- Reprint requests: Laura Toso, MD, UPDN, NICHD, NIH and NIAAA, NIH, Blg. 9 Room 1W125, 9 Memorial Drive MSC 0925, Bethesda, MD 20892-0925.
Robin Roberson, BA
- Unit on Perinatal and Developmental Neurobiology, National Institute of Child and Human Development
Jade Woodard, BS
- Unit on Perinatal and Developmental Neurobiology, National Institute of Child and Human Development
Daniel Abebe, MS
- Unit on Perinatal and Developmental Neurobiology, National Institute of Child and Human Development
Catherine Y. Spong, MD
- Unit on Perinatal and Developmental Neurobiology, National Institute of Child and Human Development

Received 7 December 2005; received in revised form 20 January 2006; accepted 24 January 2006. published online 26 April 2006.

Objective

In a model for fetal alcohol syndrome (FAS), we have previously found an alteration in NMDA receptors suggesting mediation, at least in part, of alcohol-related learning deficit. NMDA and GABA receptors interact in a multisynaptic circuit for the regulation of the inhibitory tone through the CNS. The GABA receptor subunit GABA_Aα₅ is involved in learning and is developmentally regulated, as it is excitatory in the perinatal brain and inhibitory in the adult. We were interested to evaluate alcohol's effect on GABA_Aα₅ expression to further understand alcohol-induced learning dysfunction.

Study design

Timed, pregnant C57B16/Jmice were treated on gestational day 8 with alcohol (25% alcohol, 0.03 mL/kg ip) or control (saline). Embryos and brains were harvested 10 days after treatment, and brains from adult offspring were collected after evaluation in the Morris Water Maze, a well-established test for spatial learning. Gene expression included samples from at least 3 litters per timepoint, and calibrator-normalized relative real-time polymerase chain reaction (PCR) was performed to quantify GABA_Aα₅ with GAPDH standardization. Statistical analysis included analysis of variance (ANOVA).

Results

Prenatal alcohol exposure significantly decreased GABA_Aα₅ expression in the embryo (P < .02) and fetal brains (P < .01) 10 days after therapy. However, in adult brains GABA_Aα₅ expression was increased versus controls (P < .01). As previously demonstrated, prenatal alcohol exposure resulted in deficits in adults learning the Morris Water Maze with controls learning faster (P < .05).

Conclusion

Prenatal alcohol exposure alters developmental GABA_Aα₅ expression. This may further explain the long-lasting damage of alcohol on learning skills. Both the alcohol-induced reduction in the GABA_Aα₅ subunit during development and up-regulation in adult brain may be related to learning deficits resulting in decreased learning potential caused by the developmental defect and an increased inhibition of learning resulting from increased expression as an adult. In combination with our previous findings, these suggest that alcohol-induced learning impairment is likely the result of alterations of both NMDA and GABA expression and function.

Key words: Fetal alcohol syndrome, GABA, NMDA, Mouse, Learning