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