Adolescent Ethanol Exposure Enhances NMDA Receptor-Mediated Currents in Hippocampal Neurons: Reversal by Gabapentin

H S Swartzwelder,Maeng-Hee Park,Shawn Acheson

doi:10.1038/s41598-017-12956-6

Abstract

Adolescent intermittent ethanol (AIE) exposure compromises neural function into adulthood. We have reported that astrocyte-secreted thrombospondins, and their target neuronal receptors (α2δ−1) are upregulated in the hippocampus in adulthood after AIE, suggesting aberrant excitatory synaptogenesis and hyperexcitability in memory-related circuits. Gabapentin antagonizes the interaction of thrombospondins (TSPs) with the α2δ−1 receptor, and thus may reverse or ameliorate the effects of AIE on hippocampal function. Adolescent rats were exposed to AIE or vehicle. In adulthood, hippocampal slices were prepared. Half of the slices from each animal were pre-incubated in normal artificial cerebrospinal fluid (aCSF) while half were pre-incubated in aCSF containing gabapentin. Whole-cell voltage clamp recordings were then made from CA1 pyramidal cells in normal aCSF. Evoked, N-methyl-D-aspartate (NMDA) receptor-mediated currents were recorded at baseline, and after application of the GluN2B antagonist, RO25–6981. Current amplitudes were higher in neurons from AIE-exposed animals. However, no amplitude increase was observed in neurons from slices that had been pre-incubation in gabapentin. GluN2B antagonism reduced NMDA receptor-mediated currents more efficaciously in cells from AIE-exposed animals, an effect that was also reversed by pre-incubation in gabapentin. These findings identify a mechanism underlying the enduring effects of AIE, and a clinically-utilized agent that may ameliorate those effects.

Highlights

We have recently reported elevations of astrocyte-secreted thrombospondins (TSPs) in hippocampal area CA1 25 days after adolescent intermittent ethanol (AIE) exposure in rats[15], as well as lowered thresholds for the induction of long-term potentiation (LTP) in that region[16]
Consistent with our initial hypotheses, CA1 pyramidal cells recorded in slices from Adolescent intermittent ethanol (AIE) exposed animals generated NMDA receptor-mediated eEPSCs of greater amplitude than did neurons from control animals, and these were more potently inhibited by RO25–6981 in slices from AIE exposed animals than in those from AIE or distilled water (AIW) animals
The principal findings in this report are that, 1) AIE caused both an increase in the amplitude of NMDA receptor-mediated eEPSCs in hippocampal CA1 pyramidal cells and an increase in the proportion of those currents that was driven by GluN2B receptors, and 2) both of those AIE effects were reversed by pre-incubation of hippocampal slices in artificial cerebrospinal fluid (aCSF) containing gabapentin

Summary

Introduction

We have recently reported elevations of astrocyte-secreted thrombospondins (TSPs) in hippocampal area CA1 25 days after adolescent intermittent ethanol (AIE) exposure in rats[15], as well as lowered thresholds for the induction of long-term potentiation (LTP) in that region[16]. This is noteworthy because certain TSPs are known to promote the genesis of excitatory synapses, which could underlie hyperexcitability. Combined with the increased LTP induction by mild stimulus trains and neuronal loss in hippocampal area CA1 after AIE16, these findings suggest that AIE may induce a state of elevated susceptibility to hyperexcitability and possible liability to excitotoxic cell loss, possibly through unscheduled astrocyte-mediated excitatory synaptogenesis.

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Conclusion