Age-related changes in the endocannabinoid system in the mouse hippocampus

• 2-Arachidonoylglycerol levels decrease during aging in the hippocampus.
• The expression and protein level of DAGLa, the major synthesizing enzyme of 2-AG in the brain, is decreased during aging in the hippocampus.
• The activity of MAGL, the major degrading enzyme of 2-AG, is increased in the hippocampus of aged mice.
• DAGLα decrease during aging is restricted to specific brain regions.
• CB1 mRNA expression does not change in the hippocampus during aging.

Previous studies have demonstrated that the endocannabinoid system significantly influences the progression of brain ageing, and the hippocampus is one of the brain regions most vulnerable to ageing and neurodegeneration. We have further examined age-related changes in the hippocampal endocannabinoid system by measuring the levels of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in young and old mice from two different mouse strains. We found a decrease in 2-AG but not AEA levels in aged mice. In order to identify the cause for 2-AG level changes, we investigated the levels of several enzymes that contribute to synthesis and degradation of 2-AG in the hippocampus. We found a selective decrease in DAGLα mRNA and protein levels as well as an elevated MAGL activity during ageing. We hypothesize that the observed decrease of 2-AG levels is probably caused by changes in DAGLα expression and MAGL activity. This finding can contribute to the existing knowledge about the processes underlying selective vulnerability of the hippocampus to ageing and age-related neurodegeneration.