Diacylglycerol Lipase-Alpha Regulates Hippocampal-Dependent Learning and Memory Processes in Mice

Area of Science:

• Neuroscience
• Molecular Biology
• Behavioral Pharmacology

Background:

• Diacylglycerol lipase-α (DAGL-α) is the primary enzyme for synthesizing 2-arachidonylglycerol (2-AG), an endogenous cannabinoid.
• DAGL-α is crucial for CB1 receptor-mediated synaptic plasticity and hippocampal neurogenesis.
• The role of DAGL-α in global hippocampal-mediated processes, particularly spatial learning and memory, is largely unknown.

Purpose of the Study:

• To investigate the role of DAGL-α in hippocampal long-term potentiation (LTP).
• To examine the impact of DAGL-α disruption on hippocampal-dependent spatial learning and memory tasks.
• To analyze the effects of DAGL-α manipulation on endocannabinoid and related lipid production in the brain.

Main Methods:

• Utilized complementary pharmacologic and genetic approaches to inhibit or delete the DAGL-α enzyme in male mice.
• Assessed LTP in the CA1 region of the hippocampus.
• Evaluated spatial learning and memory using the Morris Water Maze (MWM) and Object Location assays.
• Measured levels of 2-AG and related lipids in various brain regions.

Main Results:

• Both DAGL-α gene deletion (DAGL-α-/- mice) and pharmacological inhibition disrupted hippocampal CA1 LTP.
• DAGL-α-/- mice exhibited profound impairments in the Object Location assay and MWM acquisition, employing nonspatial strategies.
• WT mice treated with a DAGL-α inhibitor (DO34) showed delayed MWM acquisition and reversal learning but no deficits in memory expression, extinction, forgetting, or perseveration, nor in the Object Location task.
• Synaptic plasticity and MWM performance deficits correlated with decreased 2-AG and arachidonic acid, and increased DAGL-α precursor levels in multiple brain regions.

Conclusions:

• Constitutive or short-term disruption of DAGL-α impairs learning and memory at both electrophysiological and selective in vivo levels.
• DAGL-α plays a critical role in the integration of new spatial information.
• Genetic deletion and pharmacological inhibition of DAGL-α have differential effects on spatial memory tasks, suggesting distinct roles in memory processes.