RT Journal Article
T1 Prenatal exposure to cannabinoids evokes long-lastingfunctional alterations by targeting CB1 receptors ondeveloping cortical neurons
A1 Salas Quiroga, Adán de
A1 Díaz Alonso, Javier
A1 García-Rincón, Daniel
A1 Remmers, Floortje
A1 Vega, David
A1 Gómez Cañas, María
A1 Lutz, Beat
A1 Guzmán, Manuel
A1 Galve Roperh, Ismael
AB The CB1 cannabinoid receptor, the main target of Δ9 -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.
PB National Academy of Sciences
SN 0027-8424, ESSN: 1091-6490
YR 2015
FD 2015-11
LK https://hdl.handle.net/20.500.14352/23488
UL https://hdl.handle.net/20.500.14352/23488
LA eng
NO Ministerio de Economía y Competitividad (MINECO)
NO Comunidad de Madrid
NO Instituto de Salud Carlos III
NO German Research Foundation (Bonn, Germany)
NO Universidad Complutense de Madrid
NO Fundación Alicia Koplowitz (Madrid, España)
DS Docta Complutense
RD 17 abr 2025