Orchestrated activation of mGluR5 and CB1 promotes neuroprotection

Abstract

The metabotropic glutamate receptor 5 (mGluR5) and the cannabinoid receptor 1 (CB1) exhibit a functional interaction, as CB1 regulates pre-synaptic glutamate release and mGluR5 activation increases endocannabinoid synthesis at the post-synaptic site. Since both mGluR5 and CB1 promote neuroprotection, we delineated experiments to investigate a possible link between CB1 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 CB1 can abrogate both CB1- and mGluR5-mediated neuroprotection against glutamate insult. Interestingly, decreased glutamate release and diminished intracellular Ca2+ do not appear to play a role in CB1 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 CB1 the presynaptic site, intact signaling of both receptors is required to effectively promote neuronal survival. In conclusion, mGluR5 and CB1 act in concert to activate neuroprotective cell signaling pathways and promote neuronal survival.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0259-6) contains supplementary material, which is available to authorized users.

Enhanced Akt/GSK‐3β/CREB signaling mediates the anti‐inflammatory actions of mGluR5 positive allosteric modulators in microglia and following traumatic brain injury in male mice

“…However, studies indicate that other signal transduction pathways may also play a central role in the modulation of gene expression by mGluR5 (Bhakar, Dolen, & Bear, 2012; Osterweil, Krueger, Reinhold, & Bear, 2010; Richter, Bassell, & Klann, 2015; Stoppel et al, 2017). One alternative pathway activated by mGluR5 is PI3K/Akt (Batista et al, 2016; Shah, Silverstein, Singh, & Kumar, 2012). Akt, a serine/threonine‐specific protein kinase, can regulate diverse physiological functions, ranging from metabolism to cell survival (Manning & Cantley, 2007).…”

Differential mechanisms of tolerance induced by NMDA and 3,5‐dihydroxyphenylglycine (DHPG) preconditioning

“…The interaction between group I mGlu receptors and the endocannabinoid system in the CA1 hippocampal region has been extensively explored (Batista et al, 2016;Landucci et al, 2009).…”

The mGluR5 positive allosteric modulator VU0409551 improves synaptic plasticity and memory of a mouse model of Huntington's disease

“…, ; Batista et al . ). Interestingly, although BACHD mice only exhibit overt neuronal cell death at 12 months of age, memory deficits can be observed as early as 6 months of age (Gray et al .…”

“…Regarding HD, we previously demonstrated that chronic treatment for 18 weeks of a transgenic mouse model of HD, the BACHD mice, with the mGluR5 PAM 3-Cyano-N-(1,3diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) prevents neuronal cell loss, decreases HTT aggregate formation and rescues memory deficits (Doria et al 2015). Moreover, we have also demonstrated that mGluR5 stimulation by CDPPB can activate cell signaling pathways that are important for neuronal survival and synaptic plasticity, including extracellular signal-regulated kinase (ERK) and brain-derived neurotrophic factor (BDNF) (Doria et al 2015(Doria et al , 2013Batista et al 2016). Interestingly, although BACHD mice only exhibit overt neuronal cell death at 12 months of age, memory deficits can be observed as early as 6 months of age (Gray et al 2008;Doria et al 2015), indicating that earlier alterations other than neuronal cell death might play a role in HD-related memory disturbance.…”