Neuronal substrates and functional consequences of prenatal cannabis exposure

Abstract

Cannabis remains one of the world's most widely used substance of abuse amongst pregnant women. Trends of the last 50 years show an increase in popularity in child-bearing women together with a constant increase in cannabis potency. In addition, potent herbal "legal" highs containing synthetic cannabinoids that mimic the effects of cannabis with unknown pharmacological and toxicological effects have gained rapid popularity amongst young adults. Despite the surge in cannabis use during pregnancy, little is known about the neurobiological and psychological consequences in the exposed offspring. In this review, we emphasize the importance of maternal programming, defined as the intrauterine presentation of maternal stimuli to the foetus, in neurodevelopment. In particular, we focus on cannabis-mediated maternal adverse effects, resulting in direct central nervous system alteration or sensitization to late-onset chronic and neuropsychiatric disorders. We compare clinical and preclinical experimental studies on the effects of foetal cannabis exposure until early adulthood, to stress the importance of animal models that permit the fine control of environmental variables and allow the dissection of cannabis-mediated molecular cascades in the developing central nervous system. In sum, we conclude that preclinical experimental models confirm clinical studies and that cannabis exposure evokes significant molecular modifications to neurodevelopmental programs leading to neurophysiological and behavioural abnormalities.

Fig. 1

Main physiological effects of in utero cannabis exposure in human and animal studies. a Overview of the major physiological complications found in prenatal cannabis exposure from human longitudinal studies: (1) the Generation “R” study, (2) the OPPS study and (3) the MHPC study. b List of comparable animal studies directly (bold) or indirectly, reflecting physiological findings from human studies

Fig. 2

Molecular mechanisms of THC signalling in developing neurons. a Endocannabinoid signalling in developing neurons in relation to SCG10. The growth cone is a 2-AG-rich domain due to low levels of MAGL. Within the stabilized axon, MAGL accumulates and prevents excess 2-AG from engaging CB₁Rs. However, THC can induce ectopic CB₁R signalling since MAGL is unable to degrade it. Note that 2-AG can either be synthesized from DAGLs within the growth cone (autocrine) or be released from neighbouring cells (paracrine). Since the role of AEA signalling during axonal elongation and pathfinding is poorly understood, the AEA signalling machinery is colour-coded in grey [110]. b Exposure of THC to developing foetal neurons results in c-Jun terminal kinase (JNK) phosphorylation leading to SCG10 degradation and microtubule stabilization. This, together with the internalization of CB₁Rs (leading to overall less signalling events) results in changes to neuronal morphology and eventually to altered brain circuit formation (i inside and o outside the cell membrane)