%0 Journal Article
%A De Salas Quiroga, Adán
%A Díaz Alonso, Javier
%A García Rincón, Daniel
%A Remmers, Floortje
%A Vega, David
%A Gómez Cañas, María
%A Lutz, Beat
%A Guzmán Pastor, Manuel
%A Ismael Galve-Roperh
%A Galve Roperh, Ismael
%T Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB1 receptors on developing cortical neurons
%D 2015
%@ 0027-8424
%@ 1091-6490
%U https://hdl.handle.net/20.500.14352/93369
%X The CB1 cannabinoid receptor, the main target of Δ9-tetrahydrocan nabinol (THC), the most prominent psychoactive compound ofmarijuana, plays a crucial regulatory role in brain development asevidenced by the neurodevelopmental consequences of its manip ulation in animal models. Likewise, recreational cannabis use duringpregnancy affects brain structure and function of the progeny.However, the precise neurobiological substrates underlying the con sequences of prenatal THC exposure remain unknown. As CB1 sig naling is known to modulate long-range corticofugal connectivity,we analyzed the impact of THC exposure on cortical projectionneuron development. THC administration to pregnant mice in arestricted time window interfered with subcerebral projectionneuron generation, thereby altering corticospinal connectivity, andproduced long-lasting alterations in the fine motor performance ofthe adult offspring. Consequences of THC exposure were reminis cent of those elicited by CB1 receptor genetic ablation, and CB1-nullmice were resistant to THC-induced alterations. The identity of em bryonic THC neuronal targets was determined by a Cre-mediated,lineage-specific, CB1 expression-rescue strategy in a CB1-null back ground. Early and selective CB1 reexpression in dorsal telencephalicglutamatergic neurons but not forebrain GABAergic neurons res cued the deficits in corticospinal motor neuron development ofCB1-null mice and restored susceptibility to THC-induced motoralterations. In addition, THC administration induced an increasein seizure susceptibility that was mediated by its interference withCB1-dependent regulation of both glutamatergic and GABAergicneuron development. These findings demonstrate that prenatal ex posure to THC has long-lasting deleterious consequences in theadult offspring solely mediated by its ability to disrupt the neuro developmental role of CB1 signaling
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