Dissociation of the pharmacological effects of THC by mTOR blockade

The potential therapeutic benefits of cannabinoid compounds have raised interest in understanding the molecular mechanisms that underlie cannabinoid-mediated effects. We previously showed that the acute amnesic-like effects of delta9-tetrahydrocannabinol (THC) were prevented by the subchronic inhibition of the mammalian target of rapamycin (mTOR) pathway. In the present study, we assess the relevance of the mTOR pathway in other acute and chronic pharmacological effects of THC. The rapamycin derivative temsirolimus, an inhibitor of the mTOR pathway approved by the Food and Drug Administration, prevents both the anxiogenic- and the amnesic-like effects produced by acute THC. In contrast, THC-induced anxiolysis, hypothermia, hypolocomotion, and antinociception are not sensitive to the mTOR inhibition. In addition, a clear tolerance to THC-induced anxiolysis, hypothermia, hypolocomotion, and antinociception was observed after chronic treatment, but not to its anxiogenic- and amnesic-like effects. Temsirolimus pre-treatment prevented the amnesic-like effects of chronic THC without affecting the downregulation of CB1 receptors (CB1R) induced by this chronic treatment. Instead, temsirolimus blockade after chronic THC cessation did not prevent the residual cognitive deficit produced by chronic THC. Using conditional knockout mice lacking CB1R in GABAergic or glutamatergic neurons, we found that GABAergic CB1Rs are mainly downregulated under chronic THC treatment conditions, and CB1-GABA-KO mice did not develop cognitive deficits after chronic THC exposure. Therefore, mTOR inhibition by temsirolimus allows the segregation of the potentially beneficial effects of cannabinoid agonists, such as the anxiolytic and antinociceptive effects, from the negative effects, such as anxiogenic- and amnesic-like responses. Altogether, these results provide new insights for targeting the endocannabinoid system in order to prevent possible side effects.EP and AB-G were recipients of a predoctoral fellowship, Ministerio de Educación y Cultura. This work was supported by grants from the Ministerio de Ciencia e Innovación (#SAF2009-07309 to AO and # SAF2011-29864 to RM), Instituto de Salud Carlos III (RD06/0001/0001 to RM), PLAN E/n(Plan Español para el Estímulo de la Economía y el Empleo), the European Commission/n(PHECOMP #LSHM-CT-2007-037669 to RM), Generalitat de Catalunya (SGR-2009-00731/nto RM), INSERM to GM, European Research Council (ENDOFOOD, ERC-2010-StG-/n260515, to GM), Fondation pour la Recherche Medicale to GM, and ICREA (Institució Catalana de Recerca i Estudis Avançats) Academia to R

mTOR signaling in proteostasis and its relevance to autism spectrum disorders

Proteins are extremely labile cellular components, especially at physiological temperatures. The appropriate regulation of protein levels, or proteostasis, is essential for all cells. In the case of highly polarized cells like neurons, proteostasis is also crucial at synapses, where quick confined changes in protein composition occur to support synaptic activity and plasticity. The accurate regulation of those cellular processes controlling protein synthesis and degradation is necessary for proteostasis, and its deregulation has deleterious consequences in brain function. Alterations in those cellular mechanisms supporting synaptic protein homeostasis have been pinpointed in autism spectrum disorders such as tuberous sclerosis, neurofibromatosis 1, PTEN-related disorders, fragile X syndrome, MECP2 disorders and Angelman syndrome. Proteostasis alterations in these disorders share the alterations in mechanistic/mammalian target of rapamycin (mTOR) signaling pathway, an intracellular pathway with key synaptic roles. The aim of the present review is to describe the recent literature on the major cellular mechanisms involved in proteostasis regulation in the synaptic context, and its association with mTOR signaling deregulations in various autism spectrum disorders. Altogether, the cellular and molecular mechanisms in synaptic proteostasis could be the foundation for novel shared therapeutic strategies that would take advantage of targeting common disorder mechanisms.This review was supported by grant BFU2015-68568-P (MINECO/FEDER, EU) to AO