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

  1. Adán de Salas-Quirogaa,b,c,1,
  2. Javier Díaz-Alonsoa,b,c,1,2,
  3. Daniel García-Rincóna,b,c,
  4. Floortje Remmersd,
  5. David Vegaa,c,
  6. María Gómez-Cañasa,b,e,
  7. Beat Lutzd,
  8. Manuel Guzmána,b,c, and
  9. Ismael Galve-Roperha,b,c,3

    aCentro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28049 Madrid, Spain;
  1. Edited by Leslie Lars Iversen, University of Oxford, Oxford, United Kingdom, and approved September 16, 2015 (received for review August 3, 2015)


Marijuana is the most commonly used illicit drug, and its consumption constitutes a serious health concern. The psychoactivity of the plant is exerted by its cannabinoid constituents, especially Δ9-tetrahydrocannabinol (THC), which acts by engaging CB1 cannabinoid receptors. Despite the large knowledge accumulated on how THC affects the adult brain, its molecular and functional impact on neuronal development remains obscure. This study demonstrates that remarkable detrimental consequences of embryonic THC exposure on adult-brain function, which are evident long after THC withdrawal, are solely due to the impact of THC on CB1 receptors located on developing cortical neurons. Our findings thus delineate the risk of cannabis consumption during pregnancy and contribute to identify precise neuronal lineages targeted by prenatal THC exposure.


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 CB1signaling 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.

The only thing lacking in this study is the issue of dose response relationship.  How much drug is the fetus exposed to when the mother smokes pot?  If the typical ditchweed is used, very little, but if edibles are used, or the mother is dependent on the drug, a great deal, since it  i s stored in ffat and doesn’t cross the fetal/placental barrier.

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