GABAergic inhibitory efficiency and adult neurogenesis in the hippocampus of aged Ts65Dn mice, a model of ‘Alzheimer’s disease in Down syndrome’, after chronic treatment with the monoacylglycerol lipase inhibitor JZL184

Recently we observed that chronic suppression of monoacylglycerol lipase with the selective blocker JZL184 increased brain levels of endocannabinoid 2-arachidonoil glycerol (2-AG), restored long-term potentiation, improved cognition, and reduced brain levels of Aβ40 and Aβ42 in aged Ts65Dn mice, a model of ‘Alzheimer’s disease in Down syndrome’ (ADDS). In this proposal, we plan to examine the mechanisms responsible for the restoration of cognition and synaptic plasticity in the ADDS model mice. We suggest that two types of changes resulting from JZL184-treatment may contribute synergistically to the improvements in cognition and synaptic plasticity: (I) An increase of the level of 2-AG may result in a reduction of efficiency of the inhibitory GABAergic neurotransmission and, possibly, in improvement of adult neurogenesis. (II) The decrease of hippocampal levels of Aβ40 and Aβ42, which may reduce inhibitory efficiency and improve synaptic plasticity.

Working Hypothesis: Enhancement of synaptic plasticity and cognition in aged Ts65Dn mice by chronic blockade of monoacylglycerol lipase (MAGL) is caused by persistent alterations in properties of GABAergic synapses and changes in adult neurogenesis.