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Acute Cannabinoids Impair Working Memory through Astroglial CB1 Receptor Modulation of Hippocampal LTD

2012; Cell Press; Volume: 148; Issue: 5 Linguagem: Inglês

10.1016/j.cell.2012.01.037

1097-4172

Jing Han, Philip Kesner, Mathilde Metna‐Laurent, Tingting Duan, Lin Xu, François Georges, Muriel Koehl, Djoher Nora Abrous, Juan Mendizabal‐Zubiaga, Pedro Grandes, Qing-song Liu, Guang Bai, Wei Wang, Lize Xiong, Wei Ren, Giovanni Marsicano, Xia Zhang,

Sleep and Wakefulness Research

SummaryImpairment of working memory is one of the most important deleterious effects of marijuana intoxication in humans, but its underlying mechanisms are presently unknown. Here, we demonstrate that the impairment of spatial working memory (SWM) and in vivo long-term depression (LTD) of synaptic strength at hippocampal CA3-CA1 synapses, induced by an acute exposure of exogenous cannabinoids, is fully abolished in conditional mutant mice lacking type-1 cannabinoid receptors (CB1R) in brain astroglial cells but is conserved in mice lacking CB1R in glutamatergic or GABAergic neurons. Blockade of neuronal glutamate N-methyl-D-aspartate receptors (NMDAR) and of synaptic trafficking of glutamate α-amino-3-hydroxy-5-methyl-isoxazole propionic acid receptors (AMPAR) also abolishes cannabinoid effects on SWM and LTD induction and expression. We conclude that the impairment of working memory by marijuana and cannabinoids is due to the activation of astroglial CB1R and is associated with astroglia-dependent hippocampal LTD in vivo.PaperFlickeyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiI3YzMxYTIwZjE2MThiYThkMzg3OTg5ZTMwZTI0YTJlMiIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNzI5ODgyODQ5fQ.C6HJk87sIusqQe6K22MrzmTvriUmyZ6Zpi058CCoiCy131faXW_gSWb9zLrAMqtEAHZ1wrOKWu4aA2EIHXiSTHp3DnGaNap0mXvBqHL8ATNzNu8kcHnMmwIxdKMhUjY3Hb14-DDC6sQGMuSc8gAl_Lv9_x7wDXVKoTK24e9BhISLkw7DbbCGlCbf3eeIr04xJU4LeqbUP-_wu5-I5EMI4x5H2teUWmZh36c8yvJk66B0vzPCdicppgQc3bxg-vjXCNB9igloVHvGE6pBfLTm6IYw9CNSAxMtQqktXjSkcyUWnLcrPRQrbkdjVxsUTZ2bR7agu5NWIbm-D4xFeqBUVQDownload video (mp4, 21 MB)Graphical abstractGraphical AbstractHighlights► Systemic cannabinoids activate astroglial CB1 receptors in the hippocampus in vivo ► Astroglial CB1 receptors promote the activation of postsynaptic glutamate receptors ► Activation of glutamate receptors induces long-term depression of synaptic strength ► Long-term depression is associated with impairment of spatial working memory