Abstract
Genetic alterations or pharmacological treatments affecting endocannabinoid signaling have profound effects on synaptic and neuronal properties and, under certain conditions, may improve higher brain functions. Down syndrome (DS), a developmental disorder caused by triplication of chromosome 21, is characterized by deficient cognition and inevitable development of the Alzheimer disease (AD) type pathology during aging. Here we used JZL184, a selective inhibitor of monoacylglycerol lipase (MAGL), to examine the effects of chronic MAGL inhibition on the behavioral, biochemical, and synaptic properties of aged Ts65Dn mice, a genetic model of DS. In both Ts65Dn mice and their normosomic (2N) controls, JZL184-treatment increased brain levels of 2-arachidonoylglycerol (2-AG) and decreased levels of its metabolites such as arachidonic acid, prostaglandins PGD2, PGE2, PGFα, and PGJ2. Enhanced spontaneous locomotor activity of Ts65Dn mice was reduced by the JZL184-treatement to the levels observed in 2N animals. Deficient long-term memory was also improved, while short-term and working types of memory were unaffected. Furthermore, reduced hippocampal long-term potentiation (LTP) was increased in the JZL184-treated Ts65Dn mice to the levels observed in 2N mice. Interestingly, changes in synaptic plasticity and behavior were not observed in the JZL184-treated 2N mice suggesting that the treatment specifically attenuated the defects in the trisomic animals. The JZL184-treatment also reduced the levels of Aβ40 and Aβ42, but had no effect on the levels of full length APP and BACE1 in both Ts65Dn and 2N mice. These data show that chronic MAGL inhibition improves the behavior and brain functions in a DS model suggesting that pharmacological targeting of MAGL may be considered as a perspective new approach for improving cognition in DS.
Highlights
Genetic alterations or pharmacological treatments affecting brain levels of endocannabinoids have profound effects on synaptic and neuronal properties and, under certain some conditions, may improve higher brain functions
We expected that this dose of JZL184 would selectively inhibit monoacylglycerol lipase (MAGL) and would not affect the activity of fatty acid amid hydrolase (FAAH), the primary enzyme hydrolyzing endocannabinoid anandamide (AEA) [37]
A smaller cohort of mice was injected with JZL184 at a dose of 40 mg/kg, which presumably suppressed the activity of both MAGL and FAAH [37]
Summary
Genetic alterations or pharmacological treatments affecting brain levels of endocannabinoids have profound effects on synaptic and neuronal properties and, under certain some conditions, may improve higher brain functions. Genetic or pharmacological suppression of MAGL activity results in a robust increase of the brain levels of 2-AG and a concomitant reduction of arachidonic acid and downstream eicosanoid metabolites [4, 5, 6]. Inhibition of MAGL may simultaneously increase levels of 2-AG, resulting in activation of cannabinoid receptors, and reduce the release of eicosanoids, resulting in suppression of proinflammatory signaling in the nervous system. MAGL KO mice exhibited increased synaptic plasticity and memory [8], suggesting that disruption of MAGL activity could positively affect higher brain functions. Genetic [9] or pharmacological [7] inactivation of MAGL robustly suppressed accumulation of b-amyloid (Ab) in a mouse AD model
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