The CB₁ cannabinoid receptor signals striatal neuroprotection via a PI3K/Akt/mTORC1/BDNF pathway.

C Blázquez,P Pruunsild,B Lutz,A Chiarlone,L Bellocchio,T Timmusk,D García-Rincón,M Sendtner,I Galve-Roperh,M Guzmán,E Resel

doi:10.1038/cdd.2015.11

Abstract

The CB1 cannabinoid receptor, the main molecular target of endocannabinoids and cannabis active components, is the most abundant G protein-coupled receptor in the mammalian brain. In particular, the CB1 receptor is highly expressed in the basal ganglia, mostly on terminals of medium-sized spiny neurons, where it plays a key neuromodulatory function. The CB1 receptor also confers neuroprotection in various experimental models of striatal damage. However, the assessment of the physiological relevance and therapeutic potential of the CB1 receptor in basal ganglia-related diseases is hampered, at least in part, by the lack of knowledge of the precise mechanism of CB1 receptor neuroprotective activity. Here, by using an array of pharmacological, genetic and pharmacogenetic (designer receptor exclusively activated by designer drug) approaches, we show that (1) CB1 receptor engagement protects striatal cells from excitotoxic death via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin complex 1 pathway, which, in turn, (2) induces brain-derived neurotrophic factor (BDNF) expression through the selective activation of BDNF gene promoter IV, an effect that is mediated by multiple transcription factors. To assess the possible functional impact of the CB1/BDNF axis in a neurodegenerative-disease context in vivo, we conducted experiments in the R6/2 mouse, a well-established model of Huntington's disease, in which the CB1 receptor and BDNF are known to be severely downregulated in the dorsolateral striatum. Adeno-associated viral vector-enforced re-expression of the CB1 receptor in the dorsolateral striatum of R6/2 mice allowed the re-expression of BDNF and the concerted rescue of the neuropathological deficits in these animals. Collectively, these findings unravel a molecular link between CB1 receptor activation and BDNF expression, and support the relevance of the CB1/BDNF axis in promoting striatal neuron survival.

Highlights

The CB1 receptor is the most abundant G protein-coupled receptor in the mammalian brain.[1]
Studies conducted in the mouse and rat brain have reported a close association between CB1 receptor activity and the expression of brainderived neurotrophic factor (BDNF),[5,7] one of the master neurotrophins in the mammalian forebrain.[10]
The CB1 cannabinoid receptor is a pleiotropic G protein-coupled receptor that modulates various pathways potentially involved in the control of cell survival such as phosphatidylinositol 3-kinase (PI3K)/Akt, mitogen-activated protein kinases (extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38) and cAMP/protein kinase A (PKA).[23]

Summary

Introduction

The CB1 receptor is the most abundant G protein-coupled receptor in the mammalian brain.[1]. The CB1 receptor is very highly expressed in GABAergic terminals of the forebrain, where it mediates endocannabinoid-dependent inhibition of GABA release.[1] In concert with this well-established neuromodulatory function, one of the most remarkable biological actions of the CB1 receptor is to prevent neuronal death. This effect has been reported in many different animal models of acute brain damage and chronic neurodegeneration, and has raised hope about the possible clinical use of cannabinoids as neuroprotective drugs.[1,4,5,6] the assessment of the physiological relevance and therapeutic potential of the CB1 receptor in neurological diseases is hampered, at least in part, by the lack of knowledge on the precise molecular mechanisms of CB1 receptor neuroprotective activity.[5,7] It is well established that.

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Conclusion