Orchestrated activation of mGluR5 and CB(1) promotes neuroprotection

The metabotropic glutamate receptor 5 (mGluR5) and the cannabinoid receptor 1 (CB(1)) exhibit a functional interaction, as CB(1) regulates pre-synaptic glutamate release and mGluR5 activation increases endocannabinoid synthesis at the post-synaptic site. Since both mGluR5 and CB(1) promote neuroprotection, we delineated experiments to investigate a possible link between CB(1) and mGluR5 activation in the induction of neuroprotection using primary cultured corticostriatal neurons. We find that either the pharmacological blockade or the genetic ablation of either mGluR5 or CB(1) can abrogate both CB(1)- and mGluR5-mediated neuroprotection against glutamate insult. Interestingly, decreased glutamate release and diminished intracellular Ca(2+) do not appear to play a role in CB(1) and mGluR5-mediated neuroprotection. Rather, these two receptors work cooperatively to trigger the activation of cell signaling pathways to promote neuronal survival, which involves MEK/ERK1/2 and PI3K/AKT activation. Interestingly, although mGluR5 activation protects postsynaptic terminals and CB(1) the presynaptic site, intact signaling of both receptors is required to effectively promote neuronal survival. In conclusion, mGluR5 and CB(1) act in concert to activate neuroprotective cell signaling pathways and promote neuronal survival. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13041-016-0259-6) contains supplementary material, which is available to authorized users.