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Proc Natl Acad Sci U S A. 2014 Jun 3;111(22):8257-62. doi: 10.1073/pnas.1400988111. Epub 2014 May 19.

A restricted population of CB1 cannabinoid receptors with neuroprotective activity.

Author information

1
Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas, Instituto Ramón y Cajal de Investigación Sanitaria, 28040 Madrid, Spain;Department of Biochemistry and Molecular Biology I, Instituto Universitario de Investigación Neuroquímica, Complutense University, 28040 Madrid, Spain;
2
NeuroCentre Magendie U862, Endocannabinoids and Neuroadaptation, Institut National de la Santé et de la Recherche Médicale, 33077 Bordeaux, France;NeuroCentre Magendie U862, University of Bordeaux, 33077 Bordeaux, France;
3
Department of Biochemistry and Molecular Biology IV, Complutense University, 28040 Madrid, Spain;
4
Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas, Instituto Ramón y Cajal de Investigación Sanitaria, 28040 Madrid, Spain;Department of Biochemistry and Molecular Biology III, Instituto Universitario de Investigación Neuroquímica, Complutense University, 28040 Madrid, Spain;
5
Research Unit, Hospital Universitario Fundación Alcorcón, 28922 Madrid, Spain; and.
6
Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, 55099 Mainz, Germany.
7
Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas, Instituto Ramón y Cajal de Investigación Sanitaria, 28040 Madrid, Spain;Department of Biochemistry and Molecular Biology I, Instituto Universitario de Investigación Neuroquímica, Complutense University, 28040 Madrid, Spain; mgp@bbm1.ucm.es.

Abstract

The CB1 cannabinoid receptor, the main molecular target of endocannabinoids and cannabis active components, is the most abundant G protein-coupled receptor in the mammalian brain. Of note, CB1 receptors are expressed at the synapses of two opposing (i.e., GABAergic/inhibitory and glutamatergic/excitatory) neuronal populations, so the activation of one and/or another receptor population may conceivably evoke different effects. Despite the widely reported neuroprotective activity of the CB1 receptor in animal models, the precise pathophysiological relevance of those two CB1 receptor pools in neurodegenerative processes is unknown. Here, we first induced excitotoxic damage in the mouse brain by (i) administering quinolinic acid to conditional mutant animals lacking CB1 receptors selectively in GABAergic or glutamatergic neurons, and (ii) manipulating corticostriatal glutamatergic projections remotely with a designer receptor exclusively activated by designer drug pharmacogenetic approach. We next examined the alterations that occur in the R6/2 mouse, a well-established model of Huntington disease, upon (i) fully knocking out CB1 receptors, and (ii) deleting CB1 receptors selectively in corticostriatal glutamatergic or striatal GABAergic neurons. The data unequivocally identify the restricted population of CB1 receptors located on glutamatergic terminals as an indispensable player in the neuroprotective activity of (endo)cannabinoids, therefore suggesting that this precise receptor pool constitutes a promising target for neuroprotective therapeutic strategies.

KEYWORDS:

excitotoxicity; neuromodulation; neuroprotection

Comment in

PMID:
24843137
PMCID:
PMC4050577
DOI:
10.1073/pnas.1400988111
[Indexed for MEDLINE]
Free PMC Article

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