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

Rusconi, Francesco; Rubino, Tiziana; Battaglioli, Elena

doi:10.3390/ijms21176252

Cited by 13 publications

(6 citation statements)

References 70 publications

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“…Remarkably, the LSD1/neuroLSD1 ratio can also be modulated in response to environmental stress, a process that is likely controlled by the same splicing factors, nSR100/SRRM4 and NOVA1 (Rusconi et al, 2016;Longaretti et al, 2020b). In particular, we showed that activity-induced splicing modulation causes a transient shift of LSD1/neuroLSD1 ratio in favor of LSD1 that is instrumental to negative feedback, ultimately reducing glutamatergic synaptic excitability (Rusconi and Battaglioli, 2018;Longaretti et al, 2020b;Rusconi et al, 2020). Transient increase of LSD1 activity fosters repression of a transcriptional pathway controlling the immediate early genes (IEGs) and two negative regulators of the endocannabinoid system, MAGL and ABHD6 (Longaretti et al, 2020a).…”

Section: Introductionmentioning

confidence: 68%

Evolution Increases Primates Brain Complexity Extending RbFOX1 Splicing Activity to LSD1 Modulation

et al. 2022

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Recent branching (100 MYA) of the mammalian evolutionary tree has enhanced brain complexity and functions at the putative cost of increased emotional circuitry vulnerability. Thus, to better understand psychopathology, a burden for the modern society, novel approaches should exploit evolutionary aspects of psychiatric-relevant molecular pathways. A handful of genes is nowadays tightly associated to psychiatric disorders. Among them, neuronal-enriched RbFOX1 modifies the activity of synaptic regulators in response to neuronal activity, keeping excitability within healthy domains. We here dissect a higher primates-restricted interaction between RbFOX1 and the transcriptional corepressor Lysine Specific Demethylase 1 (LSD1/KDM1A). A single nucleotide variation (AA to AG) in LSD1 gene appeared in higher primates and humans, endowing RbFOX1 with the ability to promote the alternative usage of a novel 39 AG splice site, which extends LSD1 exon E9 in the upstream intron (E9-long). Exon E9-long regulates LSD1 levels by Nonsense-Mediated mRNA Decay. As reintroduction of the archaic LSD1 variant (AA) abolishes E9-long splicing, the novel 39 AG splice site is necessary for RbFOX1 to control LSD1 levels. LSD1 is a homeostatic immediate early genes (IEGs) regulator playing a relevant part in environmental stress-response. In primates and humans, inclusion of LSD1 as RbFOX1 target provides RbFOX1 with the additional ability to regulate the IEGs. These data, together with extensive RbFOX1 involvement in psychiatric disorders and its stress-dependent regulation in male mice, suggest the RbFOX1-LSD1-IEGs axis as an evolutionary recent psychiatric-relevant pathway. Notably, outside the nervous system, RbFOX2-dependent LSD1 modulation could be a candidate deregulated mechanism in cancer.

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Section: Introductionmentioning

confidence: 68%

Evolution Increases Primates Brain Complexity Extending RbFOX1 Splicing Activity to LSD1 Modulation

et al. 2022

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“…Therefore, it is possible that both mechanisms exist in the prefrontal cortex leading to increased 2-AG level. However, while the “acute” mechanism has been associated with the initial response to stress, a fight-or-flight survival mechanism, the “sustained” mechanism has been associated with long-term effects of stress, leading, for example, to memory impairment [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

Motor-like Tics are Mediated by CB2 Cannabinoid Receptor-dependent and Independent Mechanisms Associated with Age and Sex

et al. 2022

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AbstractΔ9-Tetrahydrocannabinol (Δ9-THC) inhibits tics in individuals with Tourette syndrome (TS). Δ9-THC has similar affinities for CB1/CB2 cannabinoid receptors. However, the effect of HU-308, a selective CB2 receptor agonist, on repetitive behaviors has not been investigated. The effects of 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced motor-like tics and Δ9-THC were studied with gene analysis. The effects of HU-308 on head twitch response (HTR), ear scratch response (ESR), and grooming behavior were compared between wildtype and CB2 receptor knockout (CB2−/−) mice, and in the presence/absence of DOI or SR141716A, a CB1 receptor antagonist/inverse agonist. The frequency of DOI-induced repetitive behaviors was higher in CB2−/− than in wildtype mice. HU-308 increased DOI-induced ESR and grooming behavior in adult CB2−/− mice. In juveniles, HU-308 inhibited HTR and ESR in the presence of DOI and SR141716A. HU-308 and beta-caryophyllene significantly increased HTR. In the left prefrontal cortex, DOI increased transcript expression of the CB2 receptor and GPR55, but reduced fatty acid amide hydrolase (FAAH) and α/β-hydrolase domain-containing 6 (ABHD6) expression levels. CB2 receptors are required to reduce 5-HT2A/2C-induced tics in adults. HU-308 has an off-target effect which increases 5-HT2A/2C-induced motor-like tics in adult female mice. The increased HTR in juveniles induced by selective CB2 receptor agonists suggests that stimulation of the CB2 receptor may generate motor tics in children. Sex differences suggest that the CB2 receptor may contribute to the prevalence of TS in boys. The 5-HT2A/2C-induced reduction in endocannabinoid catabolic enzyme expression level may explain the increased endocannabinoids’ levels in patients with TS.

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“…However, recent in silico evidence indicates that CBD can bind to and inhibit TET1, potentially regulating DNA demethylation [ 82 ]. It is, however, possible that the changes in DNAm result from the regulation of neurotransmitter release by cannabinoids, which can indirectly regulate the activity or gene expression levels of enzymes involved with the DNAm process [ 83 , 84 ].…”

Section: Discussionmentioning

confidence: 99%

The Cannabis-Induced Epigenetic Regulation of Genes Associated with Major Depressive Disorder

Sayed

Joca

Starnawska

2022

Genes

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The prevalence of depression is increasing worldwide, as is the number of people suffering from treatment-resistant depression; these patients constitute 30% of those treated. Unfortunately, there have not been significant advances in the treatment of this disorder in the past few decades. Exposure to cannabis and cannabis-derived compounds impacts depression symptomatology in different ways, with evidence indicating that cannabidiol has antidepressant effects; there have been mixed results with medical cannabis. Even though the exact molecular mechanisms of the action underlying changes in depression symptomatology upon exposure to cannabis and cannabis-derived compounds are still unknown, there is strong evidence that these agents have a widespread impact on epigenetic regulation. We hypothesized that exposure to cannabis or cannabis-derived compounds changes the DNA methylation levels of genes associated with depression. To test this hypothesis, we first performed a literature search to identify genes that are differentially methylated upon exposure to cannabis and cannabis-derived compounds, as reported in methylome-wide association studies. We next checked whether genes residing in loci associated with depression, as identified in the largest currently available genome-wide association study of depression, were reported to be epigenetically regulated by cannabis or cannabis-related compounds. Multiple genes residing in loci associated with depression were found to be epigenetically regulated by exposure to cannabis or cannabis-derived compounds. This epigenomic regulation of depression-associated genes by cannabis or cannabis-derived compounds was reported across diverse organisms, tissues, and developmental stages and occurred in genes crucial for neuronal development, functioning, survival, and synapse functioning, as well as in genes previously implicated in other mental disorders.

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

Cited by 13 publications

References 70 publications

Evolution Increases Primates Brain Complexity Extending RbFOX1 Splicing Activity to LSD1 Modulation

Evolution Increases Primates Brain Complexity Extending RbFOX1 Splicing Activity to LSD1 Modulation

Motor-like Tics are Mediated by CB2 Cannabinoid Receptor-dependent and Independent Mechanisms Associated with Age and Sex

The Cannabis-Induced Epigenetic Regulation of Genes Associated with Major Depressive Disorder

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