title: Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB1 receptors on developing cortical neurons.
abstract: The CB1 cannabinoid receptor, the main target of Δ(9)-tetrahydrocannabinol (THC), the most prominent psychoactive compound of marijuana, plays a crucial regulatory role in brain development as evidenced by the neurodevelopmental consequences of its manipulation in animal models. Likewise, recreational cannabis use during pregnancy affects brain structure and function of the progeny. However, the precise neurobiological substrates underlying the consequences of prenatal THC exposure remain unknown. As CB1 signaling is known to modulate long-range corticofugal connectivity, we analyzed the impact of THC exposure on cortical projection neuron development. THC administration to pregnant mice in a restricted time window interfered with subcerebral projection neuron generation, thereby altering corticospinal connectivity, and produced long-lasting alterations in the fine motor performance of the adult offspring. Consequences of THC exposure were reminiscent of those elicited by CB1 receptor genetic ablation, and CB1-null mice were resistant to THC-induced alterations. The identity of embryonic THC neuronal targets was determined by a Cre-mediated, lineage-specific, CB1 expression-rescue strategy in a CB1-null background. Early and selective CB1 reexpression in dorsal telencephalic glutamatergic neurons but not forebrain GABAergic neurons rescued the deficits in corticospinal motor neuron development of CB1-null mice and restored susceptibility to THC-induced motor alterations. In addition, THC administration induced an increase in seizure susceptibility that was mediated by its interference with CB1-dependent regulation of both glutamatergic and GABAergic neuron development. These findings demonstrate that prenatal exposure to THC has long-lasting deleterious consequences in the adult offspring solely mediated by its ability to disrupt the neurodevelopmental role of CB1 signaling.
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28049 Madrid, Spain; Instituto de Investigación Sanitaria Ramón y Cajal (IRYCIS), 28034 Madrid, Spain; Department of Biochemistry and Molecular Biology I, Complutense University, 28040 Madrid, Spain;
authors.forename: Adán
authors.initials: A
authors.lastname: de Salas-Quiroga
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28049 Madrid, Spain; Instituto de Investigación Sanitaria Ramón y Cajal (IRYCIS), 28034 Madrid, Spain; Department of Biochemistry and Molecular Biology I, Complutense University, 28040 Madrid, Spain;
authors.forename: Javier
authors.initials: J
authors.lastname: Díaz-Alonso
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28049 Madrid, Spain; Instituto de Investigación Sanitaria Ramón y Cajal (IRYCIS), 28034 Madrid, Spain; Department of Biochemistry and Molecular Biology I, Complutense University, 28040 Madrid, Spain;
authors.forename: Daniel
authors.initials: D
authors.lastname: García-Rincón
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, 55128 Mainz, Germany;
authors.forename: Floortje
authors.initials: F
authors.lastname: Remmers
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28049 Madrid, Spain; Department of Biochemistry and Molecular Biology I, Complutense University, 28040 Madrid, Spain;
authors.forename: David
authors.initials: D
authors.lastname: Vega
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28049 Madrid, Spain; Instituto de Investigación Sanitaria Ramón y Cajal (IRYCIS), 28034 Madrid, Spain; Department of Biochemistry and Molecular Biology III, Complutense University, 28040 Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Gómez-Cañas
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, 55128 Mainz, Germany;
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28049 Madrid, Spain; Instituto de Investigación Sanitaria Ramón y Cajal (IRYCIS), 28034 Madrid, Spain; Department of Biochemistry and Molecular Biology I, Complutense University, 28040 Madrid, Spain;
authors.forename: Manuel
authors.initials: M
authors.lastname: Guzmán
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28049 Madrid, Spain; Instituto de Investigación Sanitaria Ramón y Cajal (IRYCIS), 28034 Madrid, Spain; Department of Biochemistry and Molecular Biology I, Complutense University, 28040 Madrid, Spain; igr@quim.ucm.es.
authors.forename: Ismael
authors.identifier: http://orcid.org/0000-0003-3501-2434
authors.initials: I
authors.lastname: Galve-Roperh
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000254:growth & development / Q000378:metabolism*; D013759:Dronabinol / Q000008:administration & dosage*; D005260:Female; D018811:Maternal Exposure; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D011247:Pregnancy; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*
chemical_list: D043884:Receptor, Cannabinoid, CB1; D013759:Dronabinol
keywords: CB1 cannabinoid receptor; cannabis; corticospinal; neurodevelopment; seizures