A SINGLE DAY OF ETHANOL EXPOSURE DURING DEVELOPMENT HAS PERSISTENT EFFECTS ON BI-DIRECTIONAL PLASTICITY, N-METHYL-D-ASPARTATE RECEPTOR FUNCTION AND ETHANOL SENSITIVITY Y. IZUMI, R. KITABAYASHI, M. FUNATSU, M. IZUMI, C. YUEDE, R. E. HARTMAN, D. F. WOZNIAK AND C. F. ZORUMSKI* Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA Abstract—To determine factors that contribute to the learn- ing deficits observed in individuals with fetal alcohol syn- drome, we examined the effects of early postnatal ethanol exposure on forms of synaptic plasticity thought to underlie memory. Treatment of rat pups with ethanol on postnatal day 7 impaired the induction of N-methyl-D-aspartate receptor- dependent long-term potentiation and abolished homosynap- tic long-term depression in the CA1 region of hippocampal slices prepared at postnatal day 30. An N-methyl-D-aspartate receptor-independent form of long-term potentiation induced by very high frequency stimulation could be induced in slices from ethanol-treated rats. Defects in long-term depression correlated with a diminished contribution of ifenprodil-sensi- tive N-methyl-D-aspartate receptors to synaptic transmission and defects in a spontaneous alternation behavioral task. Rats exposed to ethanol on postnatal day 7 also exhibited diminished sensitivity of synaptic N-methyl-D-aspartate re- ceptors to block by ethanol at postnatal day 30 and de- creased behavioral sedation to systemic ethanol injections. These results indicate that changes in synaptic plasticity and N-methyl-D-aspartate receptor function are likely to provide a neural substrate for the cognitive and behavioral changes that follow developmental ethanol exposure. © 2005 Pub- lished by Elsevier Ltd on behalf of IBRO. Key words: ethanol, ifenprodil, synapses, memory, plasticity, neurodevelopment. Exposure to therapeutic or abused depressant drugs for several hours on a single day during the period of devel- opmental synaptogenesis results in significant neuronal loss throughout the rodent forebrain (Ikonomidou et al., 1999, 2000; Jevtovic-Todorovic et al., 2003). These find- ings are of clinical interest because humans exposed to ethanol in utero display a cluster of physical, cognitive and behavioral abnormalities known as fetal alcohol syndrome (FAS) (Clarren and Smith, 1978) or fetal alcohol effects (FAE) when milder manifestations are observed. Children and adolescents exposed to ethanol during prenatal de- velopment have a high prevalence of neuropsychological problems including deficits in learning and memory (Olson et al., 1998; Mattson and Riley, 1999). As they mature, these individuals are also at increased risk for developing major psychiatric illnesses including substance abuse, mood and psychotic disorders (Famy et al., 1998). Thus, ethanol or other depressant drug exposure during neuro- development may represent an important environmental factor contributing to the pathogenesis of adult psychiatric disorders. Although factors contributing to the spectrum of find- ings in individuals with FAS/FAE are uncertain, recent studies indicate that ethanol and CNS depressant drug exposure on a single day during the first postnatal week in rodents, a time corresponding to the third trimester of pregnancy and the first several years of postnatal life in humans, greatly increases apoptotic neuronal death in many brain regions (Ikonomidou et al., 1999, 2000). In cases of severe damage, this developmental neuronal loss has adverse effects on brain function and development as animals mature (Jevtovic-Todorovic et al., 2003). In par- ticular, studies examining the effects of clinically used anesthetic drugs found changes in spatial reference learn- ing, spatial working memory and hippocampal long-term potentiation (LTP). The most profound defects were ob- served in rats treated with a combination of agents that depress NMDA receptor function and that augment GABA- mediated inhibition (Jevtovic-Todorovic et al., 2003). Be- cause ethanol is an N-methyl-D-aspartate receptor (NMDAR) antagonist that also augments GABAergic inhibition in some regions of the CNS and is the agent responsible for FAS, we focused the present studies on determining the effects of ethanol exposure in young postnatal rats on synaptic and behavioral outcomes as the animals matured to adolescence. EXPERIMENTAL PROCEDURES Ethanol treatment Based on prior studies (Ikonomidou et al., 2000; Wozniak et al., 2004), postnatal day (P) 7 Sprague–Dawley albino rats were administered two single injections of 2.5 g/kg ethanol s.c. two hours apart. This ethanol treatment results in a transient blood ethanol concentration of about 500 mg/dl one hour after the sec- ond injection and a level of about 200 mg/dl that is sustained for several hours (Ikonomidou et al., 2000; Wozniak et al., 2004). *Corresponding author. Tel: +1-314-747-2680; fax: +1-314-747-2682. E-mail address: zorumskc@psychiatry.wustl.edu (C. F. Zorumski). Abbreviations: ACSF, artificial cerebrospinal fluid; ANOVA, analysis of variance; APV, 2-amino-5-phosphonovalerate; CNQX, 6-cyano-7-nit- roquinoxaline-2,3-dione; EPSPs, excitatory postsynaptic potentials; FAE, fetal alcohol effects; FAS, fetal alcohol syndrome; LTD, long- term depression; LTP, long-term potentiation; NMDAR, N-methyl-D- aspartate receptor; P, postnatal day. Neuroscience 136 (2005) 269 –279 0306-4522/05$30.00+0.00 © 2005 Published by Elsevier Ltd on behalf of IBRO. doi:10.1016/j.neuroscience.2005.07.015 269