Dendritic remodeling of hippocampal neurons is associated with altered NMDA receptor expression in alcohol dependent rats

Abstract

Prolonged alcohol exposure has been previously shown to impair the structure and function of the hippocampus, although the underlying structural and biochemical alterations contributing to these deleterious effects are unclear. Also unclear is whether these changes persist into prolonged periods of abstinence. Previous work from our lab utilizing a clinically relevant rodent model of alcohol consumption demonstrated that alcohol dependence (induced by chronic intermittent ethanol vapor exposure or CIE) decreases proliferation and survival of neural stem cells in the hippocampal subgranular zone and hippocampal neurogenesis in the dentate gyrus, implicating this region of the cortex as particularly sensitive to the toxic effects of prolonged ethanol exposure. For this study, we investigated seven weeks of CIE-induced morphological changes (dendritic complexity and dendritic spine density) of dentate gyrus (DG) granule cell neurons, CA3, and CA1 pyramidal neurons and the associated alterations in biochemical markers of synaptic plasticity and toxicity (NMDA receptors and PSD-95) in the hippocampus in ethanol-experienced Wistar rats 3h (CIE) and 21 days (protracted abstinence) after the last ethanol vapor exposure. CIE reduced dendritic arborization of DG neurons and this effect persisted into protracted abstinence. CIE enhanced dendritic arborization of pyramidal neurons and this effect did not persist into protracted abstinence. The architectural changes in dendrites did not correlate with alterations in dendritic spine density, however, they were associated with increases in the expression of pNR2B, total NR2B, and total NR2A immediately following CIE with expression levels returning to control levels in prolonged abstinence. Overall, these data provide the evidence that CIE produces profound changes in hippocampal structural plasticity and in molecular tools that maintain hippocampal structural plasticity, and these alterations may underlie cognitive dysfunction associated with alcohol dependence. In addition, the compensatory state concurrent with reduced plasticity during protracted abstinence could leave the hippocampus vulnerable to subsequent insult following chronic ethanol exposure.

Ethanol-Associated Changes in Glutamate Reward Neurocircuitry: A Minireview of Clinical and Preclinical Genetic Findings

“…Recent research indicates that alcohol and/or drugs of abuse have a profound developmental effect on the PSD as well 174,177,178 ; such that, similar to earlier reports on the vulnerability of the adolescent hippocampus to alcohol and/or drug exposure, 175,176 there is a differential effect of binge-like ethanol exposure between adolescent and adult rats. Risher et al 177 reported that adolescent intermittent ethanol (AIE) exposure in rats reduced PSD-95 expression levels in the hippocampus, leading to the retention of immature-like dendritic spine phenotypes into adulthood.…”

“…However, these authors indicated that adult CIE could alter dendritic complexity in a subregion-specific manner, with a partial return to basal levels after protracted abstinence. 178 Taken together these studies suggest that the PSD-95, and glutamate activity, may be more vulnerable to ethanol-induced changes during adolescence than during adulthood and that adolescent ethanol-induced changes in PSD-95 may interfere with the maturation of dendritic spines. Similarly, considerable evidence indicates a crucial role for Shank and Homer proteins in neuroplasticity as well as alcohol and drug dependence.…”

“…There was also a reduction in the number of VGlut1/PSD-95 and VGlut1/SAP102 (another MAGUK) colocalized synaptic puncta and these effects were driven by decreases in PSD-95 and SAP102 density with no effect on presynaptic VGlut1 expression levels. 177 In contrast, chronic intermittent ethanol (CIE) during adulthood 178 did not alter PSD-95 expression in the hippocampus as a whole. However, these authors indicated that adult CIE could alter dendritic complexity in a subregion-specific manner, with a partial return to basal levels after protracted abstinence.…”

Analyses of differentially expressed genes after exposure to acute stress, acute ethanol, or a combination of both in mice

“…In the present study, changes in gene expression were examined in the hippocampus for the following reasons: 1) the hippocampus has been shown to be one of the major brain areas in the stress axis (as reviewed in McEwen, 2002; McEwen & Milner, 2007); 2) the hippocampal formation is particularly sensitive to ethanol exposure, exhibiting morphological and neurochemical changes after ethanol exposure (Beresford et al, 2006; Durazzo et al, 2011; Staples, Kim, & Mandyam, 2015); and 3) studies have used imaging technologies to examine neuroanatomical changes in individuals with post-traumatic stress disorder (PTSD) with concomitant alcohol abuse problems and demonstrated that while stress causes hippocampal deficits, alcohol abuse enhances these effects (Hedges & Woon, 2010; Starčević et al, 2015). …”

Developmental effects of wheel running on hippocampal glutamate receptor expression in young and mature adult rats

“…Procedures optimized for measuring neuronal levels of both phosphoproteins and total proteins was performed as previously described (Kim et al, 2014; Galinato et al, 2015; Navarro and Mandyam, 2015; Staples et al, 2015). Tissue was homogenized on ice by sonication in buffer (320 mM sucrose, 5 mM HEPES, 1 mM EGTA, 1 mM EDTA, 1% SDS, with Protease Inhibitor Cocktail and Phosphatase Inhibitor Cocktails II and III diluted 1:100; Sigma), heated at 100 degrees C for five minutes, and stored at −80 degrees C until determination of protein concentration by a detergent-compatible Lowry method (Bio-Rad, Hercules, CA).…”