Proteomic Analysis Demonstrates Adolescent Vulnerability to Lasting Hippocampal Changes Following Chronic Alcohol Consumption

Abstract

Background: Excessive teenage alcohol consumption is of great concern because alcohol may adversely alter the developmental trajectory of the brain. The aim of the present study was to assess whether chronic intermittent alcohol intake during the adolescent period alters hippocampal protein expression to a greater extent than during adulthood.Methods: Adolescent [postnatal day (PND) 27] and adult (PND 55) male Wistar rats were given 8 hours daily access to beer (4.44% ethanol v ⁄ v) in addition to ad libitum food and water for 4 weeks. From a large subject pool, subgroups of adolescent and adult rats were selected that displayed equivalent alcohol intake (average of 6.1 g ⁄ kg ⁄ day ethanol). The 4 weeks of alcohol access were followed by a 2-week alcohol-free washout period after which the hippocampus was analyzed using 2-DE proteomics.Results: Beer consumption by the adult group resulted in modest hippocampal changes relative to alcohol naı¨ve adult controls. The only changes observed were an up-regulation of citrate synthase (a precursor to the Krebs cycle) and fatty acid binding protein (which facilitates fatty acid metabolism). In contrast, adolescent rats consuming alcohol showed more widespread hippocampal changes relative to adolescent controls. These included an increase in cytoskeletal protein T-complex protein 1 subunit epsilon (TCP-1) and a decrease in the expression of 10 other proteins, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH), triose phosphate isomerise, alpha-enolase, and phosphoglycerate kinase 1 (all involved in glycolysis); glutamate dehydrogenase 1 (an important regulator of glutamate); methylmalonate-semialdehyde dehydrogenase (involved in aldehyde detoxification); ubiquitin carboxyl-terminal hydrolase isozyme L1 (a regulator of protein degradation); and synapsin 2 (involved in synaptogenesis and neurotransmitter release).Conclusions: These results suggest the adolescent hippocampus is more vulnerable to lasting proteomic changes following repeated alcohol exposure. The proteins most affected include those related to glycolysis, glutamate metabolism, neurodegeneration, synaptic function, and cytoskeletal structure.

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.…”

“…Regarding glutamate dehydrogenase, which metabolizes glutamate; adolescent binge-like drinking by rats resulted in a 40% decrease in hippocampal glutamate dehydrogenase 1, which was not seen in rats that received the same protocol during adulthood. 174 Given this finding, it is noteworthy that ethanol inhibits NMDA excitation and LTP to a greater extent in hippocampal slices from adolescent versus adult rats. 175,176 Therefore, significant differences in ethanol’s effects on glutamatergic activity occur across periadolescence and adulthood (see later in the chapter).…”

XRCC5 as a Risk Gene for Alcohol Dependence: Evidence from a Genome-Wide Gene-Set-Based Analysis and Follow-up Studies in Drosophila and Humans

“…According to KEGG, these processes include alcohol degradation and the conversion of the resulting acetate to acetyl CoA. In rat models, chronic alcohol consumption has been associated with changes in the enzymes of glycolysis and gluconeogenesis in the liver (Klouckova et al, 2006), as well as with enzymes of glycolysis in the hippocampus (Hargreaves et al, 2009). Research in humans has demonstrated inhibition of gluconeogenesis following alcohol ingestion, as determined through quantification of the gluconeogenic flux (Siler et al, 1998).…”

A possible role of a cerebral energy gene in alcoholism

“…Microarray analysis of fruit flies exposed to ethanol has evidenced that lipidic transport genes and fatty acid metabolism genes were altered, including the bubblegum gene (Morozova et al, 2006). Another analysis using adolescent Wistar rats revealed alterations in pathways related to metabolism and/or transport of fatty acid in the brain after chronic ethanol use (Hargreaves et al, 2009). A transcriptome meta-analysis study has found some candidate genes associated with ethanol drinking on murine chromosome nine, among them acyl-CoA synthetase bubblegum family member 1 (Acad11) and acyl-Coenzyme A dehydrogenase family member 11 (Ascbg1) (Mulligan et al, 2006).…”