Silenciamiento presináptico por el receptor cb1 de cannabinoides

Resumo

Cannabinoid type 1 receptors (CB1R) are one of the most abundant G protein-coupled receptors in the brain. They mediate short-term retrograde inhibition of neurotransmitter release, as well as long-term depression of synaptic transmission at excitatory synapses. The short-term depression (STD) effects are due to the inhibition in Ca2+ influx through voltage-gated calcium channels and the opening of potassium channels, which both reduce neuronal excitability. Long-term depression (LTD) is related to adenylate cyclase (AC) inhibition and decrease in cAMP levels (Heifets and Castillo, 2009), which targets the exocytotic machinery. LTD induction requires longer CB1R activation than STD (Chevaleyre and Castillo, 2003; Ronesi et al., 2004). Long-term effects of CB1R have been extensively studied in cerebellum. Synapses established between parallel fibers of cerebelar granule cell and Purkinje cells undergo cannabioid-induced LTD. Its induction requires prolonged exposure to cannabinoids simultaneous to parallel fiber stimulation (Safo and Regehr 2005) and its maintenance seems to be dependent on nitric oxide (NO) which is generated in the presynaptic compartment and diffuses to the postsynapsis sustaining LTD (Shibuki and Okada, 1991, Aiba et al., 1994). Previous work in the laboratory has demonstrated that synaptic boutons respond in a heterogeneous way to cannabinoids. More of the boutons show inhibited exocytotic response but a subpopulation of synaptic boutons that were previously active do not respond to depolarization behaving as silent boutons. Presynaptically silent boutons are synapses containing full complement of exocytotic release proteins that fail to release neurotransmitter in response to a strong depolarization and Ca2+ influx (Cousin and Evans, 2011; Crawford and Mennerick, 2012)...