Developmentally Regulated Actions of Alcohol on Hippocampal Glutamatergic Transmission

Abstract

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 Ca 2ϩ 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.

Ethanol Inhibits Persistent Activity in Prefrontal Cortical Neurons

“…However, results from studies from our laboratory show that, in acute slices, synaptic NMDA currents from deep-layer PFC neurons are reliably inhibited by moderate (44 mM) concentrations of ethanol whereas those generated by AMPA or GABA A receptors are mostly unaffected (our unpublished observations). These findings are generally consistent with other studies showing that ethanol has little effect on most AMPA-mediated EPSCs (Lovinger et al, 1989;Weiner et al, 1999) (but see Mameli et al, 2005;Carta et al, 2006) and has variable effects on GABA-mediated currents (for review, see Weiner and Valenzuela, 2006). Importantly, NMDA-dependent response processes are consistently reported to be inhibited by ethanol including those from hippocampus (Lovinger et al, 1990), posterior cingulate (Li et al, 2002), nucleus accumbens (Nie et al, 1994), and amygdala (Roberto et al, 2004).…”

Aniracetam Reversed Learning and Memory Deficits Following Prenatal Ethanol Exposure by Modulating Functions of Synaptic AMPA Receptors

“…The altered frequency of mEPSC is also expected to reflect the changes in the number of pre-synaptic release sites or the probability of release. Although we cannot definitely distinguish between the two, the observed reduction in frequency further supports the idea that ethanol inhibits glutamate release in the CA1 hippocampal region (Mameli et al, 2005;Hendricson et al, 2003;Maldve et al, 2004). In addition, prenatal ethanol exposure has been shown to reduce levels of BDNF protein and mRNA levels in the hippocampus (Feng et al, 2005), which can influence AMPA and NMDA receptor-mediated synaptic transmission (Aicardi et al, 2004;Kossel et al, 2001;Kang et al, 1997;Abidin et al, 2006;Rex et al, 2006).…”

“…Thus, it is possible that some of the AMPAR-mediated synaptic dysfunctions associated with prenatal ethanol exposure are caused by an ethanol-induced disruption of glutamate signaling during this migration stage. A disruption of neuronal signaling during migration might lead neurons to migrate to ectopic locations where they will either die or form dysfunctional connections (Olney et al, 2001) in the hippocampal CA3-CA1 region as well as to the reduced glutamate release (Mameli et al, 2005;Hendricson et al, 2003;Maldve et al, 2004), thereby altering AMPARmediated neurotransmission.…”

Involvement of Non-NMDA Glutamate Receptors in Central Amygdala in Synaptic Actions of Ethanol and Ethanol-Induced Reward Behavior

“…In contrast to NMDAR, AMPAR in many brain sites examined is not affected by acute ethanol (Lovinger et al, 1989;Morrisett and Swartzwelder, 1993;Nie et al, 1994;Mameli et al, 2005). Interestingly, it has been reported recently that ethanol reduces non-NMDA EPSCs in CeA neurons (Roberto et al, 2004) and inhibits…”