Cannabinoid receptors play key roles in brain function, and cannabinoid effects in brain physiology and drug-related behavior are thought to be mediated by receptors present in neurons. Neuron-astrocyte communication relies on the expression by astrocytes of neurotransmitter receptors. Yet, the expression of cannabinoid receptors by astrocytes in situ and their involvement in the neuron-astrocyte communication remain largely unknown. We show that hippocampal astrocytes express CB1 receptors that upon activation lead to phospholipase C-dependent Ca2+ mobilization from internal stores. These receptors are activated by endocannabinoids released by neurons, increasing astrocyte Ca2+ levels, which stimulate glutamate release that activates NMDA receptors in pyramidal neurons. These results demonstrate the existence of endocannabinoid-mediated neuron-astrocyte communication, revealing that astrocytes are targets of cannabinoids and might therefore participate in the physiology of cannabinoid-related addiction. They also reveal the existence of an endocannabinoid-glutamate signaling pathway where astrocytes serve as a bridge for nonsynaptic interneuronal communication.
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We thank G. Perea for her valuable assistance; W. Buño, C. Guaza, E.D. Martín, and M. Fuenzalida for critical comments on the manuscript; J. García-Marqués, A. Muñoz, and L. Mestre for their help with immunocytochemistry; and A. Zimmer for the generous gift of the CB1R knockout mice. This work was supported by grants from MEC (BFU2004-00448; BFU2007-64764), Comunidad de Madrid - CSIC (200620M083), Spain, and European Union (HEALTH-F2-2007-202167). M.N. is a FPI-MEC predoctoral fellow.