Binge-Pattern Ethanol Exposure During Adolescence, but Not Adulthood, Causes Persistent Changes in GABA_AReceptor-Mediated Tonic Inhibition in Dentate Granule Cells

Abstract

Background In recent years, it has become clear that acute ethanol affects various neurobiological and behavioral functions differently in adolescent animals than in adults. However, less is known about the long-term neural consequences of chronic ethanol exposure during adolescence, and most importantly whether adolescence represents a developmental period of enhanced vulnerability to such effects. Methods We made whole cell recordings of GABAA receptor-mediated tonic inhibitory currents from dentate gyrus granule cells (DGGCs) in hippocampal slices from adult rats that had been treated with chronic intermittent ethanol (CIE) or saline during adolescence, young adulthood, or adulthood. Results CIE reduced baseline tonic current amplitude in DGGCs from animals pre-treated with ethanol during adolescence, but not in GCs from those pre-treated with ethanol during young adulthood or adulthood. Similarly, the enhancement of tonic currents by acute ethanol exposure ex vivo was increased in GCs from animals pre-treated with ethanol during adolescence, but not in those from animals pre-treated during either of the other two developmental periods. Conclusions These findings underscore our recent report that CIE during adolescence results in enduring alterations in tonic current and its acute ethanol sensitivity and establish that adolescence is a developmental period during which the hippocampal formation is distinctively vulnerable to long-term alteration by chronic ethanol exposure.

Adolescent Alcohol Exposure Alters GABAA Receptor Subunit Expression in Adult Hippocampus

“…Using the alcohol exposure paradigm employed in the current study, it has been demonstrated that, in contrast to AIE, CIE in adulthood does not alter GABA A R mediated tonic currents recorded from dentate granule cells in the acute hippocampal slice preparation (Fleming et al 2012; 2013). We therefore examined the effect of CIE exposure during adulthood on the expression of GABA A R subunits in the hippocampus.…”

“…This pattern of expression remained evident throughout all of the experiments presented in this study. The main subunit of interest was the δ-GABA A R protein because of its association with extrasynaptic GABA receptor function and our previous electrophysiological findings related to the effects of AIE on GABA A receptor-mediated tonic current in adulthood (Fleming et al, 2012; 2013). We chose to assess the α4 and α5 GABA A R proteins because they are associated with tonic GABA A R-mediated neuronal inhibition in the hippocampal formation (see Belelli et al, 2009).…”

“…As a follow-up to the recent reports that AIE exposure attenuates tonic GABA A R-mediated currents in adulthood (Fleming et al; 2012; 2013), we examined the effect of AIE or CIE on developmental changes in the expression of GABA A R subunits that are linked to mediation of tonic and synaptic currents. However, before assessing the effects of AIE or CIE, we measured the expression of α1-, α4-, α5- and δ-GABA A R in the DRM and membrane soluble fraction isolated from the hippocampus of control (i.e.…”

“…However, despite the long-standing awareness that human adolescents and young adults consume high amounts of ethanol, studies of the long-term consequences of chronic ethanol exposure during adolescent development on hippocampal function have only now begun to emerge. For example, we have recently shown that adolescent intermittent ethanol (AIE) reduces tonic γ-aminobutyric acid A receptor (GABA A R)-mediated inhibition in the hippocampal formation in adulthood (Fleming et al, 2012; 2013), and reduces the density of the A-type K + current ( I A ) in GABAergic hippocampal interneurons (Li et al, 2013). Importantly, such long-term alterations were not observed after comparable CIE exposure during adulthood (CIE), suggesting that adolescence is a distinctively vulnerable period for such effects.…”

Neuroimmune Basis of Alcoholic Brain Damage

“…Similarly, adolescent ethanol binge models produce a long-lasting decrease in sensitivity to the sedative/motor-impairing effects of acute ethanol, i.e., an adolescent-like low response persisting into adulthood (White, Truesdale, et al, 2002). At the cellular level, adolescent alcohol exposure, but not adult, produces an enduring decrease in the magnitude of GABA receptor-mediated tonic current in dentate granule cells (Fleming, Acheson, Moore, Wilson, & Swartzwelder, 2012; Fleming et al, 2013), which is critical for maintaining the balance of excitation and inhibition within hippocampal circuits. In addition, acute ethanol induced decreases in A-type potassium current (IA) in GABAergic hippocampal interneurons, persists after adolescent ethanol treatment resulting in adolescent-like responses in adulthood (Li et al, 2013).…”