A restricted population of CB1 cannabinoid receptors with neuroprotective activity.
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.
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;
Anna
A
Chiarlone
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;
Luigi
L
Bellocchio
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;
Cristina
C
Blázquez
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;
Eva
E
Resel
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;
Edgar
E
Soria-Gómez
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;
Astrid
A
Cannich
Department of Biochemistry and Molecular Biology IV, Complutense University, 28040 Madrid, Spain;
José J
JJ
Ferrero
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;
Onintza
O
Sagredo
Research Unit, Hospital Universitario Fundación Alcorcón, 28922 Madrid, Spain; and.
Cristina
C
Benito
Research Unit, Hospital Universitario Fundación Alcorcón, 28922 Madrid, Spain; and.
Julián
J
Romero
Department of Biochemistry and Molecular Biology IV, Complutense University, 28040 Madrid, Spain;
José
J
Sánchez-Prieto
Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, 55099 Mainz, Germany.
Beat
B
Lutz
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;
Javier
J
Fernández-Ruiz
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;
Ismael
I
Galve-Roperh
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.
Manuel
M
Guzmán
D000368:Aged; D000818:Animals; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology*; D003342:Corpus Striatum / Q000166:cytology / Q000502:physiology*; D063388:Endocannabinoids / Q000378:metabolism / Q000502:physiology / Q000627:therapeutic use; D005260:Female; D059330:GABAergic Neurons / Q000378:metabolism / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D019426:Integrases / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D009498:Neurotoxins / Q000378:metabolism; D009924:Organ Culture Techniques; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011963:Receptors, GABA-A / Q000378:metabolism; D013574:Synaptosomes / Q000502:physiology
D029742:Caenorhabditis elegans Proteins; D063388:Endocannabinoids; C469698:GAB-1 protein, C elegans; D009498:Neurotoxins; D043884:Receptor, Cannabinoid, CB1; D011963:Receptors, GABA-A; D018698:Glutamic Acid; C045073:Cre recombinase; D019426:Integrases
excitotoxicity; neuromodulation; neuroprotection