AMP-Activated Protein Kinase Treatment Ameliorates Chronic Restraint Stress Induced Memory Impairment in Early Adolescent Rat by Restoring Metabolite Profile and Synaptic Proteins

Recent studies highlight the role of brain metabolites in regulation of neuronal signals and behaviour. To understand the underlying mechanism, brain metabolites and associated signaling molecules were examined in early adolescent rat experienced CRS. Rats were tested for their learning and memory ability, and their metabolite profile was evaluated using Gas chromatography-mass spectrometry (GC-MS). Differences in metabolites were examined by variable importance in projection (VIP) and multivariate analysis. Ingenuity Pathway Analysis (IPA) and KEGG ID were performed for the identified metabolites. We found that CRS altered the metabolites that were involved in biosynthesis of steroid hormone, aminoacyl t-RNA, L-Dopa biosynthesis, and metabolism of tyrosine, fatty acid, and purine. Further analysis showed reduction of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR, a metabolite involved in purine metabolism) an AMP kinase activator, influenced the hypoxanthine-guanine phosphoribosyltransferase (HPRT), serotonin transporter (SERT), postsynaptic density protein (PSD) -95, its phosphorylation and brain-derived neurotrophic factor (BDNF) in CRS animals, which displayed deficit in memory. The AICAR treated CRS rats showed improved memory and altered metabolites and other molecules (HPRT, SERT, PSD-95 and BDNF) levels were restored. Our analysis revealed that CRS induced changes in metabolites possibly altered synaptic plasticity and memory in which HPRT, SERT-PSD95-BDNF associated pathway involved. Taken together, our observation provides initial insight into how stress differently influences the metabolic pathway, and associated behaviour. Further study will help to develop pharmacological intervention strategies.