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The Journal of Neuroscience, August 31, 2005, 25(35):8027-8036; doi:10.1523/JNEUROSCI.2434-05.2005

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Cellular/Molecular
Developmentally Regulated Actions of Alcohol on Hippocampal Glutamatergic Transmission

Manuel Mameli, Paula A. Zamudio, Mario Carta, and C. Fernando Valenzuela

Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131

Ethanol exposure during fetal development is a leading cause of learning disabilities. Studies suggest that it alters learning and memory by permanently damaging the hippocampus. It is generally assumed that this is mediated, in part, via alterations in glutamatergic transmission. Although NMDA receptors are presumed to be the most sensitive targets of ethanol in immature neurons, this issue has not been explored in the developing hippocampus. We performed whole-cell patch-clamp recordings in hippocampal slices from neonatal rats. Unexpectedly, we found that acute ethanol (10–50 mM) exposure depresses inward currents elicited by local application of exogenous AMPA, but not NMDA, in CA3 pyramidal neurons. These findings revealed a direct effect of ethanol on postsynaptic AMPA receptors. Ethanol significantly decreased the amplitude of both AMPA and NMDA receptor-mediated EPSCs evoked by electrical stimulation. This effect was associated with an increase in the paired-pulse ratio and a decrease in the frequency of miniature EPSCs driven by depolarization of axonal terminals. These findings demonstrate that ethanol also acts at the presynaptic level. -Conotoxin-GVIA occluded the effect of ethanol on NMDA EPSCs, indicating that ethanol decreases glutamate release via inhibition of N-type voltage-gated Ca²⁺ channels. In more mature rats, ethanol did not affect the probability of glutamate release or postsynaptic AMPA receptor-mediated currents, but it did inhibit NMDA-mediated currents. We conclude that the mechanism by which ethanol inhibits glutamatergic transmission is age dependent and challenge the view that postsynaptic NMDA receptors are the primary targets of ethanol early in development.

Key words: development; ethanol; glutamate; presynaptic; postsynaptic; electrophysiology

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Received Feb 25, 2005; revised July 22, 2005; accepted July 25, 2005.

This article has been cited by other articles:

				L. Servais, R. Hourez, B. Bearzatto, D. Gall, S. N. Schiffmann, and G. Cheron Purkinje cell dysfunction and alteration of long-term synaptic plasticity in fetal alcohol syndrome PNAS, June 5, 2007; 104(23): 9858 - 9863. [Abstract] [Full Text] [PDF]

				Y. Tu, S. Kroener, K. Abernathy, C. Lapish, J. Seamans, L. J. Chandler, and J. J. Woodward Ethanol Inhibits Persistent Activity in Prefrontal Cortical Neurons J. Neurosci., April 25, 2007; 27(17): 4765 - 4775. [Abstract] [Full Text] [PDF]

				W. Zhu, B. Bie, and Z. Z. Pan Involvement of Non-NMDA Glutamate Receptors in Central Amygdala in Synaptic Actions of Ethanol and Ethanol-Induced Reward Behavior J. Neurosci., January 10, 2007; 27(2): 289 - 298. [Abstract] [Full Text] [PDF]

				M. Carta, M. Mameli, and C. F. Valenzuela Alcohol Potently Modulates Climbing Fiber->Purkinje Neuron Synapses: Role of Metabotropic Glutamate Receptors J. Neurosci., February 15, 2006; 26(7): 1906 - 1912. [Abstract] [Full Text] [PDF]

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