Emergence of NMDAR‐independent long‐term potentiation at hippocampal CA1 synapses following early adolescent exposure to chronic intermittent ethanol: Role for sigma‐receptors

Abstract

Adolescent humans who abuse alcohol are more vulnerable than adults to the development of memory impairments. Memory impairments often involve modifications in the ability of hippocampal neurons to establish long-term potentiation (LTP) of excitatory neurotransmission; however, few studies have examined how chronic ethanol exposure during adolescence affects LTP mechanisms in hippocampus. We investigated changes in LTP mechanisms in hippocamal slices from rats exposed to intoxicating concentrations of chronic intermittent ethanol (CIE) vapors in their period of early-adolescent (i.e., prepubescent) or late-adolescent (i.e., postpubescent) development. LTP was evaluated at excitatory CA1 synapses in hippocampal slices at 24 h after the cessation of air (control) or CIE vapor treatments. CA1 synapses in control slices showed steady LTP following induction by high-frequency stimulation, which was fully dependent on NMDAR function. By contrast, slices from early-adolescent CIE exposed animals showed a compound form of LTP consisting of an NMDAR-dependent component and a slow-developing component independent of NMDARs. These components summated to yield LTP of robust magnitude above LTP levels in age-matched control slices. Bath-application of the sigma-receptor antagonist BD1047 and the neuroactive steroid pregnenolone sulfate, but not acute ethanol application, blocked NMDAR-independent LTP, while leaving NMDAR-dependent LTP intact. Analysis of presynaptic function during NMDAR-independent LTP induction demonstrated increased presynaptic function via a sigma-receptor-dependent mechanism in slices from early-adolescent CIE-exposed animals. By contrast, CIE exposure after puberty onset in late-adolescent animals produced decrements in LTP levels. The identification of a role for sigma-receptors and neuroactive steroids in the development of NMDAR-independent LTP suggests an important pathway by which hippocampal synaptic plasticity, and perhaps memory, may be uniquely altered by chronic ethanol exposure during the prepubescent phase of adolescent development.

Previous Ethanol Experience Enhances Synaptic Plasticity of NMDA Receptors in the Ventral Tegmental Area

“…In contrast, long-term ethanol exposure has been shown to produce upregulation of NMDAR function/expression in the hippocampus (Nelson et al, 2005), amygdala (Roberto et al, 2006), and striatum (Wang et al, 2010), although it is not clear whether this leads to an enhancement of NMDAR-dependent synaptic plasticity (Stephens et al, 2005; Xia et al, 2006; Sabeti and Gruol, 2008). In the present study, we found that VTA dopamine neurons exhibit increased susceptibility to the induction of mGluR/IP 3 -dependent LTP of NMDAR EPSCs after repeated ethanol exposure in vivo .…”

Ethanol modulation of synaptic plasticity

“…However, this seems inconsistent with the withdrawal-associated hyperactivity of Schaffer collateral-CA1 synapses measured in latter studies (Hendricson et al, 2007; Thomas et al, 1998b). And more recent findings suggest that chronic exposure to a liquid diet or ethanol vapor may actually enhance LTP at CA1 glutamate synapses (Fujii et al, 2008; Sabeti and Gruol, 2008). In fact, the Sabeti and Gruol study found that the effects of chronic ethanol on LTP in this brain region are dependent upon the age of the animal during exposure, with increased LTP expression occurring in younger adolescents (28–36 days old) and decreased LTP expression found in older adolescent animals (45–50 days old).…”

Effects of Ethanol on Immune Response in the Brain: Region-Specific Changes in Adolescent Versus Adult Mice

“…A high percentage of adolescents experiment with alcohol and alcohol consumption by this population is characterized by heavy or binge drinking (SAMHSA, 2012). These phenomena are of particular concern because neuronal plasticity, synaptic remodeling, neurotransmission, and neurogenesis are highly active, alcohol-sensitive processes in the adolescent brain as demonstrated in animal models (Carpenter-Hyland and Chandler, 2007; Crews and Nixon, 2009; Pascual et al, 2009; Sabeti and Gruol, 2008). Alcohol disruption of these processes likely underlies the fact that adolescent drinking leads to increased incidence of alcohol abuse and addiction in adulthood (Alaux-Cantin et al, 2012; Hingson et al, 2006; Maldonado-Devincci et al, 2010).…”