In cultured oligodendrocyte precursor cells, 2AG was found to enhance cell proliferation and differentiation. Inhibition of DAGL, CB1 or CB2 impaired cell proliferation while CB1 and/or CB2 stimulation or MAGL inhibition increased proliferation (Gomez et al., 2015). These results suggest the ECS is fundamentally involved in CNS development and potentially in CNS maintenance/repair as well.
In rats the developmental effects of early postnatal exposure to alcohol and CP-55,940 (a synthetic THC analogue) was tested. Both alcohol and CP reduced body growth, especially in combination, although the cannabinoid effect was only short-term. Developmental cannabinoid exposure advanced early motor development, whereas alcohol exposure delayed development, and subjects given combined exposure did not differ from controls on some measures. Alcohol exposure impaired motor coordination later in life. In contrast, cannabinoid exposure, by itself did not significantly affect long-term motor coordination, but did exacerbate alcohol-related impairments in motor coordination among females. These results suggest that cannabinoid exposure may not only alter development by itself, but may exacerbate alcohol's teratogenic effects in specific behavioral domains (Breit et al., 2019a). In a different set of experiments alcohol and CP, especially in combination, showed increased locomotor activity in the open field. Alcohol, but not CP impaired spatial learning in the water maze and only CP increased time spent in the open arm of an elevated plus maze indicating reduced anxiety (Breit et al., 2019b). As the early postnatal period in rats corresponds to the 3rd trimester in human pregnancy these studies suggest that alcohol use in late fetal development, especially in combination with cannabinoids may negatively affect further development. It should be noted that results with CP do not necessarily reflect the effects of THC.
In mice, postnatal day 7 alcohol exposure induced neurodegeneration in a CB1-dependent way, involving reduced β-catenin signaling (Subbanna and Basavarajappa, 2020).
In mice, activation of CB1 receptor directly impacted on actin polymerization and stability via WAVE1 in growth cones of developing neurons, leading to their collapse, as well as in synaptic spines of mature neurons, leading to their retraction. In adult mice, CB1 receptor agonists attenuated activity-dependent remodeling of dendritic spines in spinal cord neurons in vivo and suppressed inflammatory pain by regulating the WAVE1 complex. The results suggest a role for CB1 in neuronal network formation (Njoo et al., 2015).
In cultured hippocampal neurons, CB1 inhibition, at a very early developmental stage, has no effect on axonal growth, yet CB1 activation can promote it. By contrast, subsequent dendritic growth is impaired by CB1R inhibition, which also reduces ankyrinG density at the AIS. Moreover, our data show a significant correlation between early dendritic growth and ankyrinG density. However, CB1R inhibition in later developmental stages after dendrites are formed only reduces ankyrinG accumulation at the AIS (Tapia et al., 2017). The results indicate an important role for CB1 in neuronal differentiation.
Adult mice deficient for CB1 show defects in somatosensory cortex map formation. Glutamatergic neuron-specific CB1 deficiency and dual glutamatergic/GABAergic CB1 deficiency result in increased septal area in barrel field maps but GABAergic CB1 deficiency did not change barrel field formation (Hedrich et al., 2019) suggesting a role for CB1 signaling in sensory cortex development.
The cerebellum of perinatal mice shows dynamic and spatially restricted expression of CB1, prominent at birth in pontocerebellar axons, and later in migrating and differentiating anterior vermis granule cells. Purkinje cells express DAGL and MAGL and presumably have a role in regulating 2AG. CB1 deficient mice exhibit impairments in cerebellar-influenced fine-motor, but not gross-motor behaviors (Martinez et al., 2020) suggesting a role for CB1 in cerebellar development.
In rats it was found that testosterone drives masculinization of the amygdala, leading to more masculine (rougher) play behavior. Amygdala masculinization promotes microglial phagocytosis of newborn astrocytes. This process is mediated by 2AG activation of CB1 and CB2 in the critical period of amygdala development (VanRyzin et al., 2019) indicating that the ECS plays a critical role in sex-specific amygdala and behavioral development.
Although CB2 is expressed in hematopoietic stem cells and differentiated blood cells and has a major role in the immune system, knockout studies in mice suggest CB2 is largely dispensable for normal hematopoiesis (Danner et al., 2019).
In rats injected with WIN55,212-2 (0.5 mg/kg s.c.) or THC (2 mg/kg s.c.) in the first 10 postnatal days delays KCC2 upregulation (inducing the switch from excitatory to inhibitory GABAergic neurotransmission) in a CB1-dependent manner (Scheyer et al., 2019). This suggests a developmental defect but please note that the doses were very high for human standards.
In 10-day old mouse pups, a single injection of THC (10 or 50 mg/kg, s.c.) increased CB1 expression in the parietal cortex and apoptotic factor Bax in the frontal cortex and decreased neurotrophin receptor TrkB in the hippocampus and frontal/parietal cortex. Similar results were found after acetaminophen/paracetamol injections, suggesting a shared pathway (Philippot et al., 2019). THC and paracetamol injections in pups both induced altered adult behavior. While these results suggest both THC and paracetamol can elicit severe neurodevelopmental defects in neonates, it should be noted that the used doses are very high for human standards. Interestingly, ibuprofen does not elicit the developmental defects observed with THC and paracetamol (Philippot et al., 2016).
Embryonic exposure to THC (3 mg/kg/day i.p. from embryonic day 10 to 17) leads to specific reduction of CCK-positive hippocampal interneurons (basket cells) in male, but not female offspring. This leads to altered hippocampal oscillations in the stratum pyramidale (altered theta, reduced gamma power and a slowing down of sharp wave ripples) and male-specific defects in spatial and conceptual learning (de Salas-Quiroga et al., 2020).
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Scheyer, A.F., Borsoi, M., Wager-Miller, J., Pelissier-Alicot, A.-L., Murphy, M.N., Mackie, K., and Manzoni, O.J.J. (2019). cannabinoid Exposure via Lactation in Rats Disrupts Perinatal Programming of the Gamma-Aminobutyric Acid Trajectory and Select Early-Life Behaviors. Biol. Psychiatry.
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VanRyzin, J.W., Marquardt, A.E., Argue, K.J., Vecchiarelli, H.A., Ashton, S.E., Arambula, S.E., Hill, M.N., and McCarthy, M.M. (2019). Microglial Phagocytosis of Newborn Cells Is Induced by endocannabinoids and Sculpts Sex Differences in Juvenile Rat Social Play. Neuron.