Impaired 2-AG signaling in hippocampal glutamatergic neurons: aggravation of anxiety-like behavior and unaltered seizure susceptibility.

BACKGROUND:

Postsynaptically generated 2-arachidonoylglycerol (2-AG) activates the presynaptic cannabinoid type-1 receptor (CB1R), which is involved in synaptic plasticity at both glutamatergic and GABAergic synapses. However, the differential function of 2-AG signaling at glutamatergic versus GABAergic synapses in the context of animal behavior has not been investigated yet.

METHODS:

Here, we analyzed the role of 2-AG signaling selectively in hippocampal glutamatergic neurons. Monoacylglycerol lipase (MAGL), the primary degrading enzyme of 2-AG, is expressed at presynaptic sites of excitatory and inhibitory neurons. By adeno-associated virus-mediated overexpression of MAGL in glutamatergic neurons of the mouse hippocampus, we selectively interfered with 2-AG signaling at glutamatergic synapses of these neurons.

RESULTS:

Genetic modification of MAGL resulted in a 50% decrease in 2-AG tissue levels without affecting the content of the second major endocannabinoid anandamide. A typical electrophysiological read-out for 2-AG signaling is the depolarization-induced suppression of excitation (DSE) and of inhibition (DSI), respectively. Elevated MAGL levels at glutamatergic terminals selectively impaired DSE, while DSI was not significantly changed. At the behavioral level, mice with impaired hippocampal glutamatergic 2-AG signaling exhibited increased anxiety-like behavior, but showed no alterations in aversive memory formation and seizure susceptibility.

CONCLUSION:

Our data indicate that 2-AG signaling selectively in hippocampal glutamatergic neurons is essential for the animal’s adaptation to aversive situations.
© The Author 2015. Published by Oxford University Press on behalf of CINP.