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Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB1 receptors on developing cortical neurons

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Salas Quiroga, Adán de and Díaz Alonso, Javier and García-Rincón, Daniel and Remmers, Floortje and Vega, David and Gómez Cañas, María and Lutz, Beat and Guzmán, Manuel and Galve Roperh, Ismael (2015) Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB1 receptors on developing cortical neurons. Proceedings of the National Academy of Sciences, 112 (44). pp. 13693-13698. ISSN 0027-8424, ESSN: 1091-6490

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Official URL: http://www.pnas.org/content/112/44/13693



Abstract

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.


Item Type:Article
Uncontrolled Keywords:Cannabis; CB1 cannabinoid receptor; Corticospinal neurons; Neurodevelopment; Seizures
Subjects:Medical sciences > Biology > Biochemistry
Medical sciences > Biology > Neurosciences
ID Code:46657
Deposited On:01 Mar 2018 09:25
Last Modified:02 Mar 2018 08:41

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