Cannabis affects cognitive performance through the activation of the endocannabinoid system, and the molecular mechanisms involved in this process are poorly understood. Using the novel object-recognition memory test in mice, we found that the main psychoactive component of cannabis, delta9-tetrahydrocannabinol (THC), alters short-term object-recognition memory specifically involving protein kinase C (PKC)-dependent signaling. Indeed, the systemic or intra-hippocampal pre-treatment with the PKC inhibitors, prevented the short-term, but not the long-term, memory impairment induced by THC. In contrast, systemic pre-treatment with mammalian target of rapamycin complex 1 (mTORC1) inhibitors, known to block the amnesic-like effects of THC on long-term memory, did not modify such a short-term cognitive deficit. Immunoblot analysis revealed a transient increase in PKC signaling activity in the hippocampus after THC treatment. Thus, THC administration induced the phosphorylation of a specific Ser residue in the hydrophobic-motif at the C-terminal tail of several PKC isoforms. This significant immunoreactive band that paralleled cognitive performance did not match in size with the major PKC isoforms expressed in the hippocampus except for PKCθ. Moreover, THC transiently enhanced the phosphorylation of the postsynaptic calmodulin-binding protein neurogranin in a PKC dependent manner. These data demonstrate that THC alters short-term object-recognition memory through hippocampal PKC/neurogranin signaling.

Predoctoral fellowship from the Spanish Ministry of Education (A. B-G. and E.P.). Partial support by FP7-PEOPLE-2013-IEF-623638 (A.B-G). Partial support by FRAXA Research Foundation (M.G-G.). Predoctoral fellowship by FPI (MINEICO/FEDER, EU) (V.S-M. and L.G-L). Research supported by BFU2015-68568P (A.O.), (MINECO/FEDER, UE); Redes temáticas de investigación cooperativa en salud (RETICS) del Instituto de Salud Carlos III (#RD16/0017/0020)-Red de trastornos adictivos (RTA) (R.M.); Generalitat de Catalunya, AGAUR (#2014-SGR-1547) (R.M.); ICREA (Institució Catalana de Recerca i Estudis Avançats) Acadèmia (R.M. and A.O.)