Children with fetal alcohol syndrome (FAS), suffer mental deficits that handicap them for life. Understanding how ethanol exerts its neuroteratogenic action at a cellular and molecular level may offer insights into the design of interventions to improve CNS functional outcomes for these individuals. In this regard, it is now clear that GABA/ARs are predominantly """"""""excitatory/neurotrophic"""""""" transducers in developing brain and take on the better known, classical inhibitory role as the brain matures. Early GABA/ARs depolarize immature neurons, activating voltage-dependent Ca/2+ entry and stimulating neurogenesis, neuronal differentiation, migration as well as synaptogenesis. Currently, little is known about the impact of ethanol on the function or expression of """"""""excitatory"""""""" GABA/ARs in the immature CNS. If ethanol distorts the normal developmental pattern of GABA/AR activity, this could contribute to neurological deficits in FAS. We have recently identified a delay in the postnatal evolution of GABA/ARs in rat medial septal/diagonal band (MS/DB) neurons one week after moderate """"""""binge- like"""""""" postnatal ethanol exposure. Basic GABA/AR function recovers bu 4-5 weeks of life, but subtle longer-lasting changes in Zn/2+ inhibition remain. Impairment of early postnatal GABA/AR function in the MS/DB could distort appropriate synapse formation and contribute to attention deficits characteristic of individuals with FAS. This project will use well-established in vivo rodent models of FAS, in vitro primary neuronal culture systems, immunocytochemistry, stereology and in vitro electrophysiological recordings in individual neurons and brain slices to determine the impact of prenatal ethanol exposure on MS/DB functional development. These studies will test the hypothesis that: """"""""Perinatal ethanol exposure inhibits excitatory GABA/ARs which interferes with normal patterns of neuronal development.""""""""

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Special Emphasis Panel (ZRG4-ALTX-3 (01))
Program Officer
Twombly, Dennis
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Texas A&M University
Schools of Medicine
College Station
United States
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Wang, Haiying; DuBois, Dustin W; Tobery, Angelika N et al. (2013) Long-lasting distortion of GABA signaling in MS/DB neurons after binge-like ethanol exposure during initial synaptogenesis. Brain Res 1520:36-50
DuBois, Dustin W; Damborsky, Joanne C; Fincher, Annette S et al. (2013) Varenicline and nicotine enhance GABAergic synaptic transmission in rat CA1 hippocampal and medial septum/diagonal band neurons. Life Sci 92:337-44
BaƱuelos, Cristina; Gilbert, Ryan J; Montgomery, Karienn S et al. (2012) Altered spatial learning and delay discounting in a rat model of human third trimester binge ethanol exposure. Behav Pharmacol 23:54-65
Huang, Luping Z; Hsiao, Shu-Huei; Trzeciakowski, Jerome et al. (2006) Chronic nicotine induces growth retardation in neonatal rat pups. Life Sci 78:1483-93
DuBois, Dustin W; Trzeciakowski, Jerome P; Parrish, Alan R et al. (2006) GABAergic miniature postsynaptic currents in septal neurons show differential allosteric sensitivity after binge-like ethanol exposure. Brain Res 1089:101-15
DuBois, Dustin W; Parrish, Alan R; Trzeciakowski, Jerome P et al. (2004) Binge ethanol exposure delays development of GABAergic miniature postsynaptic currents in septal neurons. Brain Res Dev Brain Res 152:199-212
Hsiao, Shu-Huei; DuBois, Dustin W; Miranda, Rajesh C et al. (2004) Critically timed ethanol exposure reduces GABAAR function on septal neurons developing in vivo but not in vitro. Brain Res 1008:69-80
Hsiao, Shu-Huei; Frye, Gerald D (2003) AMPA receptors on developing medial septum/diagonal band neurons are sensitive to early postnatal binge-like ethanol exposure. Brain Res Dev Brain Res 142:89-99
Hsiao, S H; Acevedo, J L; DuBois, D W et al. (2001) Early postnatal ethanol intubation blunts GABA(A) receptor up-regulation and modifies 3alpha-hydroxy-5alpha-pregnan-20-one sensitivity in rat MS/DB neurons. Brain Res Dev Brain Res 130:25-40