Further characterization of the effect of ethanol on voltage-gated Ca2+ channel function in developing CA3 hippocampal pyramidal neurons

Abstract

Developmental ethanol exposure damages the hippocampus, a brain region involved in learning and memory. Alterations in synaptic transmission and plasticity may play a role in this effect of ethanol. We previously reported that acute and repeated exposure to ethanol during the 3rd trimester-equivalent inhibits long-term potentiation of GABAA receptor-dependent synaptic currents in CA3 pyramidal neurons through a mechanism that depends on retrograde release of brain-derived neurotrophic factor driven by activation of voltage-gated Ca2+ channels (Zucca and Valenzuela, 2010). We found evidence indicating that voltage-gated Ca2+ channels are inhibited in the presence of ethanol, an effect that may play a role in its mechanism of action. Here, we further investigated the acute effect of ethanol on the function of voltage-gated Ca2+ channels in CA3 pyramidal neurons using Ca2+ imaging techniques. These experiments revealed that acute ethanol exposure inhibits voltage-gated Ca2+ channels both in somatic and proximal dendritic compartments. To investigate the long-term consequences of ethanol on voltage-gated Ca2+ channels, we used patch-clamp electrophysiological techniques to assess the function of L-type voltage-gated Ca2+ channels during and following ten days of vapor ethanol exposure. During ethanol withdrawal periods, the function of these channels was not significantly affected by vapor chamber exposure. Taken together with our previous findings, our results suggest that 3rd trimester-equivalent ethanol exposure transiently inhibits L-type voltage-gated Ca2+ channel function in CA3 pyramidal neurons and that compensatory mechanisms restore their function during ethanol withdrawal. Transient inhibition of these channels by ethanol may be, in part, responsible for the hippocampal abnormalities associated with developmental exposure to this agent.

Peripheral blood transcriptomic profiling indicates molecular mechanisms commonly regulated by binge-drinking and placebo-effects

“…However, Peng et al, reported a SNP (rs2500086) associated with alcohol-induced affective symptoms during alcohol withdrawal in a cohort of European Americans, that was in eQTL with RNF182 40 . Similarly, previous studies have demonstrated that alcohol transiently inhibit L-type calcium ion channels at intoxicating concentrations 41,42 . Thus, it is possible that binge drinking may inhibit L-type calcium ion channels through upregulation of CACNG6, as we have detected in this study.…”

L-Type Calcium Channels Contribute to Ethanol-Induced Aberrant Tangential Migration of Primordial Cortical GABAergic Interneurons in the Embryonic Medial Prefrontal Cortex

“…In the present study, acute exposure to ethanol enhanced the activity of LTCCs. We note that acute ethanol exposure has been shown to inhibit the function of LTCCs in several neuronal preparations (Wang et al, 1991;Wang et al, 1994;Mullikin-Kilpatrick and Treistman, 1995;Zucca et al, 2010;Mah et al, 2011;Morton et al, 2016). Such differences may arise from the fact that embryonic neurons have relatively depolarized resting membrane potentials (approximately -40 mV; Skorput et al, 2019), such that membrane depolarization exerted by traditionally hyperpolarizing neurotransmitters such as GABA might be more conducive to reaching the activation potential for LTCCs (Nakanishi and Okazawa, 2006;Horigane et al, 2019).…”

Aging in nucleus accumbens and its impact on alcohol use disorders

“…The activity of MSNs is regulated by electrical membrane properties, and dysregulation of these properties has been proposed as an important neuroadaptation underlying addiction ( Marty & Spigelman, 2012a ). In addition, ethanol regulates the activity of several voltage- and ligand-gated ion channels including voltage-dependent Na + , Ca 2+ , and K + channels, which are involved in the control of action potential and consequently neuronal activity ( Gallegos et al, 2019 ; Katsura et al, 2006 ; Kim & Suh, 2021 ; Marty & Spigelman, 2012a ; Morton & Valenzuela, 2016 ; Xiao et al, 2008 ; Zucca & Valenzuela, 2010 ). Studies revealed that acute treatment with low doses of ethanol significantly decreased action potential firing in MSNs from the nAc after applying a depolarizing current pulse in 2-month-old mice ( Gallegos et al, 2019 ; Muñoz et al, 2020 ).…”

“…Moreover, work by Kuntamallappanavar and Dopico (2016) suggests that different β subunits are responsible for different ethanol responses of BK channels, under identical recording conditions ( Kuntamallappanavar & Dopico, 2016 ). Meanwhile, studies in hippocampal neurons indicate that L-type voltage-gated Ca 2+ channels are inhibited by acute ethanol treatment, whereas chronic ethanol exposure induces upregulation of these channels ( Katsura et al, 2006 ; Morton & Valenzuela, 2016 ; Zucca & Valenzuela, 2010 ). Finally, regarding Na + voltage-gated channels, some data indicate that alcohol suppresses the activity of these channels, thus contributing to the inhibitory effect of ethanol in neurons ( Horishita & Harris, 2008 ; Xiao et al, 2008 ).…”