Characterization of cell-type specific knockout of different elements of the endocannabinoid system in cortical glutamatergic neurons in the context of stress-induced behavioral phenotype
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Abstract
Background
Chronic stress is an important factor for the development of mental health impairments, such as depression and generalized anxiety disorder. Chronic social defeat (CSD) stress is an ethologically valid model of chronic stress in rodents, combining elements of psychological and physical stress. The endocannabinoid (eCB) system plays important roles in maintaining the homeostasis of biological systems through the tuning of neuronal excitability, thereby mediating a protective role after prolonged stress exposure.
Methods
In the present study, we investigated genetically modified adult male mice where the eCB signal via anandamide (AEA) was reduced (by deletion of the AEA synthesizing enzyme NAPE-PLD) or enhanced (by deletion of the AEA degradation enzyme FAAH), as well as mice lacking the cannabinoid CB1 receptor. These genetic manipulations were induced in glutamatergic neurons of the dorsal telencephalon. After the application of CSD stress, the phenotypes of these mutant mice were investigated in a battery of behavioral tests assessing sociability, anxiety, memory, shelter-seeking behavior, and despair.
Results
We could confirm a robust anxiogenic effect of CSD in the EPM test. Interestingly, we have not observed a stress effect on the sociability of any of the mouse lines as identified in the SI test. Under non-stress conditions, we observed an anxiogenic phenotype in Glu-CB1-KO and Nex-NAPE-PLD KO, and hyperlocomotion in Nex-FAAH KO mice. Additionally, we could confirm a drastic reduction of FAAH protein levels in cortical and subcortical regions of Nex-FAAH line, and a moderate reduction of NAPE-PLD protein in cortical regions of Nex-NAPE-PLD KO mice.
Conclusions
In conclusion, genetic manipulation of the endocannabinoid system in cortical glutamatergic neurons did not result in persistent effects of prolonged stress exposure. Detected differences between the genotypes in the non-stressed groups points toward baseline differences that could mask or over-power the effect of stress.
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Journal of cannabis research, 7, Biomed Central, London, 2025, https://doi.org/10.1186/s42238-025-00368-7