Endocannabinoid-Epigenetic Cross-Talk: A Bridge toward Stress Coping.

Francesco Rusconi,Tiziana Rubino,Elena Battaglioli

doi:10.3390/ijms21176252

Francesco Rusconi, Tiziana Rubino + Show 1 more

Open Access

https://doi.org/10.3390/ijms21176252

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Abstract

There is no argument with regard to the physical and psychological stress-related nature of neuropsychiatric disorders. Yet, the mechanisms that facilitate disease onset starting from molecular stress responses are elusive. Environmental stress challenges individuals’ equilibrium, enhancing homeostatic request in the attempt to steer down arousal-instrumental molecular pathways that underlie hypervigilance and anxiety. A relevant homeostatic pathway is the endocannabinoid system (ECS). In this review, we summarize recent discoveries unambiguously listing ECS as a stress coping mechanism. As stress evokes huge excitatory responses in emotional-relevant limbic areas, the ECS limits glutamate release via 2-arachydonilglycerol (2-AG) stress-induced synthesis and retrograde cannabinoid 1 (CB1)-receptor activation at the synapse. However, ECS shows intrinsic vulnerability as 2-AG overstimulation by chronic stress rapidly leads to CB1-receptor desensitization. In this review, we emphasize the protective role of 2-AG in stress-response termination and stress resiliency. Interestingly, we discuss ECS regulation with a further nuclear homeostatic system whose nature is exquisitely epigenetic, orchestrated by Lysine Specific Demethylase 1. We here emphasize a remarkable example of stress-coping network where transcriptional homeostasis subserves synaptic and behavioral adaptation, aiming at reducing psychiatric effects of traumatic experiences.

Highlights

When the sensation of feeling under threat elicits an exceptional psychological arousal, an individual gets involved in a fearful domain of emotions and autonomic responses that cumulatively goes under the definition of stress response
Stress-induced DNA methylation [28], physiologically increased Lysine Specific Demethylase 1 (LSD1) activity might be aimed at limiting behavioral stress responses [32]. These data indicate that transcriptional homeostatic mechanisms exist in the nucleus of hippocampal neurons, being triggered in response to different stressors, in different species, limiting the same typology of neuroplastic gene transcription with converging epigenetic strategies, all finalized to decreasing negative behavioral stress-induced short- and long-term alterations. As these mechanisms concurring to epigenetic homeostatic system are commonly promoted by stress-induced glutamatergic neuron depolarization in the hippocampus, we propose to collectively refer to them as depolarization-induced suppression of transcription (DST)
We have described two homeostatic systems pertaining to distinct cellular domains of glutamatergic neurons: the long-known widely-studied endocannabinoid system, whose main importance in stress-response termination may rely on the process of depolarization-induced suppression of excitation (DSE) [5,6] and the epigenetic homeostatic system, involved in depolarization-induced suppression of transcription (DST) [7]

Summary

Introduction

When the sensation of feeling under threat elicits an exceptional psychological arousal, an individual gets involved in a fearful domain of emotions and autonomic responses that cumulatively goes under the definition of stress response. DNA methylation prevents forced swim stress-induced transactivation of EGR1 and c-FOS [28] With these experiments, the authors showed that limiting IEGs transactivation concurs to define an adaptive onset of stress-related behavioral reactions [28], unravelling the importance of homeostatic transcriptional mechanisms to healthy behavioral responses. Stress-induced DNA methylation [28], physiologically increased LSD1 activity (by decreased neuroLSD1 levels) might be aimed at limiting behavioral stress responses [32] These data indicate that transcriptional homeostatic mechanisms exist in the nucleus of hippocampal neurons, being triggered in response to different stressors, in different species (mouse and rat), limiting the same typology of neuroplastic gene transcription with converging epigenetic strategies, all finalized to decreasing negative behavioral stress-induced short- and long-term alterations. As these mechanisms concurring to epigenetic homeostatic system are commonly promoted by stress-induced glutamatergic neuron depolarization in the hippocampus, we propose to collectively refer to them as depolarization-induced suppression of transcription (DST)

ECS and Epigenetic Homeostatic System Cross-Regulation

Concluding Remarks