Cell
Volume 148, Issue 5, 2 March 2012, Pages 1039-1050
Journal home page for Cell

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

https://doi.org/10.1016/j.cell.2012.01.037Get rights and content
Under an Elsevier user license
open archive

Summary

Impairment 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.

Highlights

► 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

Cited by (0)

13

These authors contributed equally to this work

14

These authors contributed equally to this work