A deterioration of working memory is observed in people who consume drugs containing cannabinoid compounds found in cannabis leaves and buds. A team led by Giovanni Marsicano (Inserm Research Unit 862) in collaboration with a team led by Xia Zhang, has recently identified the mechanism by which these substances affect working memory. These researchers have demonstrated for the first time that the adverse effect of cannabinoids on working memory is exerted via receptors located in the glial cells (brain cells present in large numbers and scarcely studied). This effect is associated with a decrease in neural connections in the hippocampus, the region of the brain that coordinates working memory processes. These results were published in Cell on 2 March 2012.

Working memory is used perform common cognitive operations (thinking, reading, writing, calculating, etc.) on information stored temporarily (for periods ranging from a few seconds to a few minutes). This allows for the integration audio, visual and spatial information. One of the major effects of intoxication with cannabinoids is the alteration of working memory, as observed in both humans and animals. Cannabis disturbs this function, thus preventing the consumer from performing common daily tasks. Cannabinoid receptors are expressed in the glial cells of the hippocampus, a cerebral structure essential for memory modulation. The cellular mechanisms responsible for the adverse effects of cannabis on this memorization process were previously unknown.

Giovanni Marsicano and his collaborators at the Magendie Neurocentre (Inserm Research Unit 862, University of Bordeaux 2) have successfully identified a mechanism by which cannabis causes adverse effects on working memory. The researchers have demonstrated that cannabinoids, when connected to their receptors, can decrease the strength of neural connections in the hippocampus.

Cannabinoids are a group of approximately 60 compounds present in cannabis leaves and buds. They act on the brain via cannabinoid receptors. In this study, the researchers have focused on cannabinoid receptor CB1, present in large quantities in nerve terminals within the brain (see diagram below). Cannabinoid receptor CB1 is present both in neural membranes (shown in yellow) and in the membranes of astroglial cells (shown in pink) located in the hippocampus (en orange) and used to provide support for neurons.

The connection of cannabinoids (shown in green) to CB1 receptors (shown in pink) activates the transmission of glutamate signals (shown in light blue) to the glutamate receptors (shown in dark blue) of nerve terminals used to transfer information between neurons. This mechanism modulates the strength of connections between hippocampal neurons (signal depression), thereby disturbing working memory.

In order to identify the action mechanisms of cannabinoids, the researchers have evaluated spatial working memory in the presence of THC, the best known cannabinoid (shown in green). Two groups of mice were studied in which CB1 receptors had been suppressed (in astroglial and neural cells, respectively).

When CB1 receptors are suppressed only in neural cells, the presence of THC causes spatial working memory deficits. On the contrary, when CB1 receptors are suppressed only in astroglial cells, spatial working memory performance is preserved. Therefore, the CB1 receptors located in astroglial cells are responsible for the adverse effects of THC on spatial working memory.

“These in vitro and in vivo results surprisingly demonstrate the importance of the activation of the CB1 receptors of astroglial cells, and not those of neural cells, in the mediation of the effects of cannabinoids on working memory”, explains Giovanni Marsicano.

Over the past years, a large number of studies have demonstrated the interest of cannabis for the treatment of various diseases. “The description of cannabinoid-specific action mechanisms in the hippocampus should enable optimization of the therapeutic potential of cannabinoids, which is currently limited by significant adverse effects associated with their consumption”.

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Sources: Astroglial CB Receptors Mediate Cannabinoid Alterations of Synaptic Plasticity and Working Memory Jing Han, Philip Kesner, Mathilde Metna-Laurent, Tingting Duan, Lin Xu, Francois Georges, Muriel Koehl, Djoher Nora Abrous, Juan Mendizabal-Zubiaga, Pedro Grandes, Wei Ren, Giovanni Marsicano & Xia Zhang

1 College of Life Sciences, Shaanxi Normal University, Xian, 710062 PR China.
2 Institute of Mental Health Research and Departments of Psychiatry and Cellular & Molecular Medicine, University of Ottawa, Ottawa, K1Z 7K4 Canada.
3 INSERM U862 NeuroCentre Magendie, Bordeaux 33077, France.
4 University de Bordeaux Segalen, Bordeaux 33077, France.
5 Kunming Institute of Zoology, Chinese Academy of Science, Kunming, 650223 PR China.
6 School of Life Sciences, University of Science and Technology of China, Hefei 230027, PR China.
7 CNRS, Interdisciplinary Institute for Neuroscience, UMR 5297, Bordeaux 33000, France.
8 Department of Neurosciences, Faculty of Medicine and Dentistry, Basque Country University, Leioa 48940, Spain
9 These authors contributed equally to this work.

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Giovanni Marsicano, PhD
Chargé de Recherche Inserm
Unité Inserm 862 “NeuroCentre Magendie”
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