Impaired 2-AG Signaling in Hippocampal Glutamatergic Neurons: Aggravation of Anxiety-Like Behavior and Unaltered Seizure Susceptibility

Abstract

Background:Postsynaptically generated 2-arachidonoylglycerol activates the presynaptic cannabinoid type-1 receptor, which is involved in synaptic plasticity at both glutamatergic and GABAergic synapses. However, the differential function of 2-arachidonoylglycerol signaling at glutamatergic vs GABAergic synapses in the context of animal behavior has not been investigated yet.Methods:Here, we analyzed the role of 2-arachidonoylglycerol signaling selectively in hippocampal glutamatergic neurons. Monoacylglycerol lipase, the primary degrading enzyme of 2-arachidonoylglycerol, is expressed at presynaptic sites of excitatory and inhibitory neurons. By adeno-associated virus-mediated overexpression of monoacylglycerol lipase in glutamatergic neurons of the mouse hippocampus, we selectively interfered with 2-arachidonoylglycerol signaling at glutamatergic synapses of these neurons.Results:Genetic modification of monoacylglycerol lipase resulted in a 50% decrease in 2-arachidonoylglycerol tissue levels without affecting the content of the second major endocannabinoid anandamide. A typical electrophysiological read-out for 2-arachidonoylglycerol signaling is the depolarization-induced suppression of excitation and of inhibition. Elevated monoacylglycerol lipase levels at glutamatergic terminals selectively impaired depolarization-induced suppression of excitation, while depolarization-induced suppression of inhibition was not significantly changed. At the behavioral level, mice with impaired hippocampal glutamatergic 2-arachidonoylglycerol signaling exhibited increased anxiety-like behavior but showed no alterations in aversive memory formation and seizure susceptibility.Conclusion:Our data indicate that 2-arachidonoylglycerol signaling selectively in hippocampal glutamatergic neurons is essential for the animal’s adaptation to aversive situations.

The endocannabinoid system in guarding against fear, anxiety and stress

“…34). In agreement with these observations, impairment of 2-AG signalling in hippocampal glutamatergic neurons by viral overexpression of MAGL also led to decreased 2-AG levels and increased anxiety-like behaviour 63 . Conversely, pharmacological inhibition of MAGL in wild-type mice by JZL184 had anxiolytic effects under basal conditions 60,64,65 , under increased aversive conditions 66 and after CUS 60,67 .…”

Beware of your Cre‐Ation: lacZ expression impairs neuronal integrity and hippocampus‐dependent memory

“…Regarding a possible developmental interaction between lacZ expression and embryogenesis, we found that adult-induced lacZ expression also caused hippocampal volume reduction, both for AAV-mediated as well as for tamoxifen-induced expression; thus underlining the lacZ-driven specificity of the observed effects. Of note, while we did not observe structural or cognitive deficits in our Nex-Cre 1 control mice, it has recently been shown that the disruption of the Nex gene locus may result in alterations of anxiety-related behavior (Guggenhuber et al, 2016). Thus, although we cannot exclude cumulative negative effects of a disrupted Nex gene and the lacZ expression, due to the numerous control lines used, we feel confident that the marked structural changes and cognitive deficits observed for the R26R:Nex-Cre 1 mice are mainly driven by lacZ expression.…”

A moderate diet restriction during pregnancy alters the levels of endocannabinoids and endocannabinoid-related lipids in the hypothalamus, hippocampus and olfactory bulb of rat offspring in a sex-specific manner

“…For instance, a decrease in the hippocampal 2-AG level has been correlated to anxiety-related responses [51, 75, 76], and the blockade of anandamide reuptake specifically in the hippocampus produces anxiolytic effects [77]. Furthermore, increased 2-AG in hippocampus was associated to mitigation of the cognitive alterations in severely undernourished mice supplemented with a diet rich in fish oil, an important source of n-3 PUFAs [78], although the opposite has been described in an animal model of schizophrenia [79].…”