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Cannabis and synaptic reprogramming of the developing brain

Nature Reviews Neuroscience volume 22, pages 423–438 (2021)Cite this article

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Abstract

Recent years have been transformational in regard to the perception of the health risks and benefits of cannabis with increased acceptance of use. This has unintended neurodevelopmental implications given the increased use of cannabis and the potent levels of Δ9-tetrahydrocannabinol today being consumed by pregnant women, young mothers and teens. In this Review, we provide an overview of the neurobiological effects of cannabinoid exposure during prenatal/perinatal and adolescent periods, in which the endogenous cannabinoid system plays a fundamental role in neurodevelopmental processes. We highlight impaired synaptic plasticity as characteristic of developmental exposure and the important contribution of epigenetic reprogramming that maintains the long-term impact into adulthood and across generations. Such epigenetic influence by its very nature being highly responsive to the environment also provides the potential to diminish neural perturbations associated with developmental cannabis exposure.

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Fig. 1: Neurodevelopmental pattern of the endocannabinoid system in humans and rodents.
Fig. 2: Impact of developmental THC exposure on synaptic plasticity in adulthood.
Fig. 3: Overview of proposed epigenetic effects induced by exogenous cannabinoids on the developing brain and epigenetic reprogramming of the germ line.

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References

  1. Lu, H. C. & Mackie, K. Review of the endocannabinoid system. Biol. Psychiatry Cogn. Neurosci. Neuroimaging https://doi.org/10.1016/j.bpsc.2020.07.016 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Berghuis, P. et al. Hardwiring the brain: endocannabinoids shape neuronal connectivity. Science 316, 1212–1216 (2007). This study demonstrates the crucial role of the eCB signalling in axonal guidance and in the formation of accurate synaptic connections.

    CAS  PubMed  Google Scholar 

  3. Maccarrone, M., Guzmán, M., Mackie, K., Doherty, P. & Harkany, T. Programming of neural cells by (endo)cannabinoids: from physiological rules to emerging therapies. Nat. Rev. Neurosci. 15, 786–801 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Mulder, J. et al. Endocannabinoid signaling controls pyramidal cell specification and long-range axon patterning. Proc. Natl Acad. Sci. USA 105, 8760–8765 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Buckley, N. E., Hansson, S., Harta, G. & Mezey, E. Expression of the CB1 and CB2 receptor messenger RNAs during embryonic development in the rat. Neuroscience 82, 1131–1149 (1998).

    CAS  PubMed  Google Scholar 

  6. Zurolo, E. et al. CB1 and CB2 cannabinoid receptor expression during development and in epileptogenic developmental pathologies. Neuroscience 170, 28–41 (2010).

    CAS  PubMed  Google Scholar 

  7. Biegon, A. & Kerman, I. A. Autoradiographic study of pre- and postnatal distribution of cannabinoid receptors in human brain. Neuroimage 14, 1463–1468 (2001).

    CAS  PubMed  Google Scholar 

  8. Berrendero, F., Sepe, N., Ramos, J. A., Di Marzo, V. & Fernández-Ruiz, J. J. Analysis of cannabinoid receptor binding and mRNA expression and endogenous cannabinoid contents in the developing rat brain during late gestation and early postnatal period. Synapse 33, 181–191 (1999).

    CAS  PubMed  Google Scholar 

  9. Mato, S., Del Olmo, E. & Pazos, A. Ontogenetic development of cannabinoid receptor expression and signal transduction functionality in the human brain. Eur. J. Neurosci. 17, 1747–1754 (2003). This is an important study showing functional G protein coupling of CBRs in the human fetal brain.

    PubMed  Google Scholar 

  10. Romero, J. et al. Atypical location of cannabinoid receptors in white matter areas during rat brain development. Synapse 26, 317–323 (1997).

    CAS  PubMed  Google Scholar 

  11. de Salas-Quiroga, A. et al. Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB1 receptors on developing cortical neurons. Proc. Natl Acad. Sci. USA 112, 13693–13698 (2015).

    PubMed  PubMed Central  Google Scholar 

  12. Harkany, T. et al. The emerging functions of endocannabinoid signaling during CNS development. Trends Pharmacol. Sci. 28, 83–92 (2007).

    CAS  PubMed  Google Scholar 

  13. Keimpema, E., Calvigioni, D. & Harkany, T. Endocannabinoid signals in the developmental programming of delayed-onset neuropsychiatric and metabolic illnesses. Biochem. Soc. Trans. 41, 1569–1576 (2013).

    CAS  PubMed  Google Scholar 

  14. Mackie, K. Distribution of cannabinoid receptors in the central and peripheral nervous system. Handb. Exp. Pharmacol. https://doi.org/10.1007/3-540-26573-2_10 (2005).

    Article  PubMed  Google Scholar 

  15. Herkenham, M. et al. Cannabinoid receptor localization in brain. Proc. Natl Acad. Sci. USA 87, 1932–1936 (1990). This study demonstrates the anatomical expression of CB1R and its being the most abundant G protein receptor in the adult brain.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Wang, X., Dow-Edwards, D., Keller, E. & Hurd, Y. L. Preferential limbic expression of the cannabinoid receptor mRNA in the human fetal brain. Neuroscience 118, 681–694 (2003). This is the first study to characterize the distinct anatomical pattern of CNR1 expression in the human fetal brain.

    CAS  PubMed  Google Scholar 

  17. Freund, T. F., Katona, I. & Piomelli, D. Role of endogenous cannabinoids in synaptic signaling. Physiol. Rev. 83, 1017–1066 (2003).

    CAS  PubMed  Google Scholar 

  18. Marsicano, G. & Lutz, B. Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain. Eur. J. Neurosci. 11, 4213–4225 (1999).

    CAS  PubMed  Google Scholar 

  19. Ellgren, M. et al. Dynamic changes of the endogenous cannabinoid and opioid mesocorticolimbic systems during adolescence: THC effects. Eur. Neuropsychopharmacol. 18, 826–834 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Lee, T. T., Hill, M. N., Hillard, C. J. & Gorzalka, B. B. Temporal changes in N-acylethanolamine content and metabolism throughout the peri-adolescent period. Synapse 67, 4–10 (2013).

    CAS  PubMed  Google Scholar 

  21. Castillo, P. E., Younts, T. J., Chávez, A. E. & Hashimotodani, Y. Endocannabinoid signaling and synaptic function. Neuron 76, 70–81 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Kano, M., Ohno-Shosaku, T., Hashimotodani, Y., Uchigashima, M. & Watanabe, M. Endocannabinoid-mediated control of synaptic transmission. Physiol. Rev. 89, 309–380 (2009).

    CAS  PubMed  Google Scholar 

  23. Meyer, H. C., Lee, F. S. & Gee, D. G. The role of the endocannabinoid system and genetic variation in adolescent brain development. Neuropsychopharmacology 43, 21–33 (2018).

    PubMed  Google Scholar 

  24. Tortoriello, G. et al. Miswiring the brain: Δ9-tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin-2 degradation pathway. EMBO J. 33, 668–685 (2014). This study provides mechanistic evidence of the molecular underpinnings of prenatal THC exposure with regard to neuronal differentiation and axonal guidance evident in the rodent model and in the human fetal brain.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Higuera-Matas, A., Ucha, M. & Ambrosio, E. Long-term consequences of perinatal and adolescent cannabinoid exposure on neural and psychological processes. Neurosci. Biobehav. Rev. 55, 119–146 (2015).

    CAS  PubMed  Google Scholar 

  26. DiNieri, J. A. et al. Maternal cannabis use alters ventral striatal dopamine D2 gene regulation in the offspring. Biol. Psychiatry 70, 763–769 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang, X., Dow-Edwards, D., Anderson, V., Minkoff, H. & Hurd, Y. L. In utero marijuana exposure associated with abnormal amygdala dopamine D2 gene expression in the human fetus. Biol. Psychiatry 56, 909–915 (2004).

    CAS  PubMed  Google Scholar 

  28. Ellgren, M., Spano, S. M. & Hurd, Y. L. Adolescent cannabis exposure alters opiate intake and opioid limbic neuronal populations in adult rats. Neuropsychopharmacology 32, 607–615 (2007). This is the first study to demonstrate that adolescent THC exposure increases opioid self-administration in adulthood and opioid receptor signalling in the NAc.

    CAS  PubMed  Google Scholar 

  29. Spano, M. S., Ellgren, M., Wang, X. & Hurd, Y. L. Prenatal cannabis exposure increases heroin seeking with allostatic changes in limbic enkephalin systems in adulthood. Biol. Psychiatry 61, 554–563 (2007).

    CAS  PubMed  Google Scholar 

  30. Wang, X., Dow-Edwards, D., Anderson, V., Minkoff, H. & Hurd, Y. L. Discrete opioid gene expression impairment in the human fetal brain associated with maternal marijuana use. Pharmacogenomics J. 6, 255–264 (2006).

    PubMed  Google Scholar 

  31. Castaldo, P. et al. Altered regulation of glutamate release and decreased functional activity and expression of GLT1 and GLAST glutamate transporters in the hippocampus of adolescent rats perinatally exposed to Delta(9)-THC. Pharmacol. Res. 61, 334–341 (2010).

    CAS  PubMed  Google Scholar 

  32. Ferraro, L. et al. Short- and long-term consequences of prenatal exposure to the cannabinoid agonist WIN55,212-2 on rat glutamate transmission and cognitive functions. J. Neural Transm. 116, 1017–1027 (2009).

    CAS  PubMed  Google Scholar 

  33. Antonelli, T. et al. Prenatal exposure to the CB1 receptor agonist WIN 55,212-2 causes learning disruption associated with impaired cortical NMDA receptor function and emotional reactivity changes in rat offspring. Cereb. Cortex 15, 2013–2020 (2005).

    PubMed  Google Scholar 

  34. Saez, T. M., Aronne, M. P., Caltana, L. & Brusco, A. H. Prenatal exposure to the CB1 and CB2 cannabinoid receptor agonist WIN 55,212-2 alters migration of early-born glutamatergic neurons and GABAergic interneurons in the rat cerebral cortex. J. Neurochem. 129, 637–648 (2014).

    CAS  PubMed  Google Scholar 

  35. Frau, R. et al. Prenatal THC exposure produces a hyperdopaminergic phenotype rescued by pregnenolone. Nat. Neurosci. 22, 1975–1985 (2019). This study demonstrates the sex-specific impact of prenatal THC exposure on the dopaminergic system in the VTA of preadolescent male rats that increased their sensitivity to a single THC injection re-exposure. Moreover, the study shows that postnatal treatment with pregnenolone can reverse the synaptic and behavioural deficits.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Mereu, G. et al. Prenatal exposure to a cannabinoid agonist produces memory deficits linked to dysfunction in hippocampal long-term potentiation and glutamate release. Proc. Natl Acad. Sci. USA 100, 4915–4920 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Castaldo, P. et al. Prenatal exposure to the cannabinoid receptor agonist WIN 55,212-2 increases glutamate uptake through overexpression of GLT1 and EAAC1 glutamate transporter subtypes in rat frontal cerebral cortex. Neuropharmacology 53, 369–378 (2007).

    CAS  PubMed  Google Scholar 

  38. Bassani, S., Folci, A., Zapata, J. & Passafaro, M. AMPAR trafficking in synapse maturation and plasticity. Cell Mol. Life Sci. 70, 4411–4430 (2013).

    CAS  PubMed  Google Scholar 

  39. Bara, A. et al. Sex-dependent effects of in utero cannabinoid exposure on cortical function. eLife https://doi.org/10.7554/eLife.36234 (2018). In addition to demonstrating sex-specific effects of prenatal THC exposure on PFC functions and social behaviour, this study is the first to show that eCB-mediated LTD in the PFC is mediated by distinct receptors in males and females.

    Article  PubMed  PubMed Central  Google Scholar 

  40. de Salas-Quiroga, A. et al. Long-term hippocampal interneuronopathy drives sex-dimorphic spatial memory impairment induced by prenatal THC exposure. Neuropsychopharmacology 45, 877–886 (2020).

    PubMed  PubMed Central  Google Scholar 

  41. Vargish, G. A. et al. Persistent inhibitory circuit defects and disrupted social behaviour following in utero exogenous cannabinoid exposure. Mol. Psychiatry 22, 56–67 (2017).

    CAS  PubMed  Google Scholar 

  42. Grant, K. S., Conover, E. & Chambers, C. D. Update on the developmental consequences of cannabis use during pregnancy and lactation. Birth Defects Res. https://doi.org/10.1002/bdr2.1766 (2020).

    Article  PubMed  Google Scholar 

  43. Smith, A. M. et al. Prenatal marijuana exposure impacts executive functioning into young adulthood: An fMRI study. Neurotoxicol. Teratol. 58, 53–59 (2016).

    CAS  PubMed  Google Scholar 

  44. Gray, K. A., Day, N. L., Leech, S. & Richardson, G. A. Prenatal marijuana exposure: effect on child depressive symptoms at ten years of age. Neurotoxicol. Teratol. 27, 439–448 (2005).

    CAS  PubMed  Google Scholar 

  45. Leech, S. L., Larkby, C. A., Day, R. & Day, N. L. Predictors and correlates of high levels of depression and anxiety symptoms among children at age 10. J. Am. Acad. Child Adolesc. Psychiatry 45, 223–230 (2006).

    PubMed  Google Scholar 

  46. Porath, A. J. & Fried, P. A. Effects of prenatal cigarette and marijuana exposure on drug use among offspring. Neurotoxicol. Teratol. 27, 267–277 (2005).

    CAS  PubMed  Google Scholar 

  47. Sonon, K. E., Richardson, G. A., Cornelius, J. R., Kim, K. H. & Day, N. L. Prenatal marijuana exposure predicts marijuana use in young adulthood. Neurotoxicol. Teratol. 47, 10–15 (2015).

    CAS  PubMed  Google Scholar 

  48. Bergeria, C. L. & Heil, S. H. Surveying lactation professionals regarding marijuana use and breastfeeding. Breastfeed. Med. 10, 377–380 (2015).

    PubMed  PubMed Central  Google Scholar 

  49. Perez-Reyes, M. & Wall, M. E. Presence of delta9-tetrahydrocannabinol in human milk. N. Engl. J. Med. 307, 819–820 (1982).

    CAS  PubMed  Google Scholar 

  50. Baker, T. et al. Transfer of inhaled cannabis into human breast milk. Obstet. Gynecol. 131, 783–788 (2018).

    CAS  PubMed  Google Scholar 

  51. Kolb, B., Mychasiuk, R., Muhammad, A. & Gibb, R. Brain plasticity in the developing brain. Prog. Brain Res. 207, 35–64 (2013).

    PubMed  Google Scholar 

  52. Tennes, K. et al. Marijuana: prenatal and postnatal exposure in the human. NIDA Res. Monogr. 59, 48–60 (1985).

    CAS  PubMed  Google Scholar 

  53. Astley, S. J. & Little, R. E. Maternal marijuana use during lactation and infant development at one year. Neurotoxicol. Teratol. 12, 161–168 (1990).

    CAS  PubMed  Google Scholar 

  54. Spear, L. P. & File, S. E. Methodological considerations in neurobehavioral teratology. Pharmacol. Biochem. Behav. 55, 455–457 (1996).

    CAS  PubMed  Google Scholar 

  55. Campolongo, P. et al. Perinatal exposure to delta-9-tetrahydrocannabinol causes enduring cognitive deficits associated with alteration of cortical gene expression and neurotransmission in rats. Addict. Biol. 12, 485–495 (2007).

    CAS  PubMed  Google Scholar 

  56. Suárez, I. et al. Down-regulation of the AMPA glutamate receptor subunits GluR1 and GluR2/3 in the rat cerebellum following pre- and perinatal delta9-tetrahydrocannabinol exposure. Cerebellum 3, 66–74 (2004).

    PubMed  Google Scholar 

  57. Vela, G. et al. Maternal exposure to delta9-tetrahydrocannabinol facilitates morphine self-administration behavior and changes regional binding to central mu opioid receptors in adult offspring female rats. Brain Res. 807, 101–109 (1998).

    CAS  PubMed  Google Scholar 

  58. González, B. et al. Effects of perinatal exposure to delta 9-tetrahydrocannabinol on operant morphine-reinforced behavior. Pharmacol. Biochem. Behav. 75, 577–584 (2003).

    PubMed  Google Scholar 

  59. García-Gil, L., Romero, J., Ramos, J. A. & Fernández-Ruiz, J. J. Cannabinoid receptor binding and mRNA levels in several brain regions of adult male and female rats perinatally exposed to delta9-tetrahydrocannabinol. Drug. Alcohol. Depend. 55, 127–136 (1999).

    PubMed  Google Scholar 

  60. Scheyer, A. F., Borsoi, M., Pelissier-Alicot, A. L. & Manzoni, O. J. J. Perinatal THC exposure via lactation induces lasting alterations to social behavior and prefrontal cortex function in rats at adulthood. Neuropsychopharmacology https://doi.org/10.1038/s41386-020-0716-x (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Scheyer, A. F. et al. Cannabinoid exposure via lactation in rats disrupts perinatal programming of the gamma-aminobutyric acid trajectory and select early-life behaviors. Biol. Psychiatry 87, 666–677 (2020). This is the first study to demonstrate that exposure to THC during lactation delays the developmental excitatory-to-inhibitory GABA polarity switch in the rat PFC.

    CAS  PubMed  Google Scholar 

  62. Hensch, T. K. Critical period plasticity in local cortical circuits. Nat. Rev. Neurosci. 6, 877–888 (2005).

    CAS  PubMed  Google Scholar 

  63. Beggiato, S. et al. Long-lasting alterations of hippocampal GABAergic neurotransmission in adult rats following perinatal Δ9-THC exposure. Neurobiol. Learn. Mem. 139, 135–143 (2017).

    CAS  PubMed  Google Scholar 

  64. Rivera, C. et al. The K+/Cl- co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 397, 251–255 (1999).

    CAS  PubMed  Google Scholar 

  65. Kaila, K., Price, T. J., Payne, J. A., Puskarjov, M. & Voipio, J. Cation-chloride cotransporters in neuronal development, plasticity and disease. Nat. Rev. Neurosci. 15, 637–654 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Manduca, A. et al. Sex-specific behavioural deficits induced at early life by prenatal exposure to the cannabinoid receptor agonist WIN55, 212-2 depend on mGlu5 receptor signalling. Br. J. Pharmacol. 177, 449–463 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Holitzki, H., Dowsett, L. E., Spackman, E., Noseworthy, T. & Clement, F. Health effects of exposure to second- and third-hand marijuana smoke: a systematic review. CMAJ Open 5, E814–E822 (2017).

    PubMed  PubMed Central  Google Scholar 

  68. Goodwin, R. D. et al. Trends in cannabis and cigarette use among parents with children at home: 2002 to 2015. Pediatrics https://doi.org/10.1542/peds.2017-3506 (2018).

    Article  PubMed  Google Scholar 

  69. Posis, A. et al. Indoor cannabis smoke and children’s health. Prev. Med. Rep. 14, 100853 (2019).

    PubMed  PubMed Central  Google Scholar 

  70. Eiden, R. D. et al. Pre- and postnatal tobacco and cannabis exposure and child behavior problems: bidirectional associations, joint effects, and sex differences. Drug Alcohol Depend. 185, 82–92 (2018).

    PubMed  PubMed Central  Google Scholar 

  71. Renard, J., Krebs, M. O., Le Pen, G. & Jay, T. M. Long-term consequences of adolescent cannabinoid exposure in adult psychopathology. Front. Neurosci. 8, 361 (2014).

    PubMed  PubMed Central  Google Scholar 

  72. Rubino, T., Zamberletti, E. & Parolaro, D. Adolescent exposure to cannabis as a risk factor for psychiatric disorders. J. Psychopharmacol. 26, 177–188 (2012).

    CAS  PubMed  Google Scholar 

  73. Blest-Hopley, G., Colizzi, M., Giampietro, V. & Bhattacharyya, S. Is the adolescent brain at greater vulnerability to the effects of cannabis? A narrative review of the evidence. Front. Psychiatry 11, 859 (2020).

    PubMed  PubMed Central  Google Scholar 

  74. Rubino, T. et al. Adolescent exposure to THC in female rats disrupts developmental changes in the prefrontal cortex. Neurobiol. Dis. 73, 60–69 (2015).

    CAS  PubMed  Google Scholar 

  75. Cuccurazzu, B. et al. Adult cellular neuroadaptations induced by adolescent THC exposure in female rats are rescued by enhancing anandamide signaling. Int. J. Neuropsychopharmacol. 21, 1014–1024 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Silva, L., Black, R., Michaelides, M., Hurd, Y. L. & Dow-Edwards, D. Sex and age specific effects of delta-9-tetrahydrocannabinol during the periadolescent period in the rat: the unique susceptibility of the prepubescent animal. Neurotoxicol. Teratol. 58, 88–100 (2016).

    CAS  PubMed  Google Scholar 

  77. Rubino, T. et al. Chronic delta 9-tetrahydrocannabinol during adolescence provokes sex-dependent changes in the emotional profile in adult rats: behavioral and biochemical correlates. Neuropsychopharmacology 33, 2760–2771 (2008).

    CAS  PubMed  Google Scholar 

  78. Kruse, L. C., Cao, J. K., Viray, K., Stella, N. & Clark, J. J. Voluntary oral consumption of Delta(9)-tetrahydrocannabinol by adolescent rats impairs reward-predictive cue behaviors in adulthood. Neuropsychopharmacology 44, 1406–1414 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Abela, A. R., Rahbarnia, A., Wood, S., Le, A. D. & Fletcher, P. J. Adolescent exposure to Delta9-tetrahydrocannabinol delays acquisition of paired-associates learning in adulthood. Psychopharmacology 236, 1875–1886 (2019).

    CAS  PubMed  Google Scholar 

  80. Renard, J. et al. Adolescent cannabinoid exposure induces a persistent sub-cortical hyper-dopaminergic state and associated molecular adaptations in the prefrontal cortex. Cereb. Cortex 27, 1297–1310 (2017).

    PubMed  Google Scholar 

  81. Cha, Y. M., Jones, K. H., Kuhn, C. M., Wilson, W. A. & Swartzwelder, H. S. Sex differences in the effects of delta9-tetrahydrocannabinol on spatial learning in adolescent and adult rats. Behav. Pharmacol. 18, 563–569 (2007).

    CAS  PubMed  Google Scholar 

  82. Ruiz, C. M. et al. Pharmacokinetic, behavioral, and brain activity effects of Δ9-tetrahydrocannabinol in adolescent male and female rats. Neuropsychopharmacology https://doi.org/10.1038/s41386-020-00839-w (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Wiley, J. L. & Burston, J. J. Sex differences in Δ9-tetrahydrocannabinol metabolism and in vivo pharmacology following acute and repeated dosing in adolescent rats. Neurosci. Lett. 576, 51–55 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Pertwee, R. G. Cannabinoid pharmacology: the first 66 years. Br. J. Pharmacol. 147, S163–S171 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Lee, S. E., Lee, Y. & Lee, G. H. The regulation of glutamic acid decarboxylases in GABA neurotransmission in the brain. Arch. Pharm. Res. 42, 1031–1039 (2019).

    CAS  PubMed  Google Scholar 

  86. Renard, J. et al. Adolescent THC exposure causes enduring prefrontal cortical disruption of GABAergic inhibition and dysregulation of sub-cortical dopamine function. Sci. Rep. 7, 11420 (2017).

    PubMed  PubMed Central  Google Scholar 

  87. Zamberletti, E. et al. Alterations of prefrontal cortex GABAergic transmission in the complex psychotic-like phenotype induced by adolescent delta-9-tetrahydrocannabinol exposure in rats. Neurobiol. Dis. 63, 35–47 (2014).

    CAS  PubMed  Google Scholar 

  88. Rubino, T. et al. The depressive phenotype induced in adult female rats by adolescent exposure to THC is associated with cognitive impairment and altered neuroplasticity in the prefrontal cortex. Neurotox. Res. 15, 291–302 (2009).

    CAS  PubMed  Google Scholar 

  89. Zamberletti, E. et al. Long-term hippocampal glutamate synapse and astrocyte dysfunctions underlying the altered phenotype induced by adolescent THC treatment in male rats. Pharmacol. Res. 111, 459–470 (2016).

    CAS  PubMed  Google Scholar 

  90. Prini, P., Penna, F., Sciuccati, E., Alberio, T. & Rubino, T. Chronic Delta(8)-THC exposure differently affects histone modifications in the adolescent and adult rat brain. Int. J. Mol. Sci. https://doi.org/10.3390/ijms18102094 (2017). This is a comprehensive study characterizing the impact of developmental THC exposure on histone modifications in a brain region-specific and age-specific manner, leading to either transcriptional activation or repression.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Batool, S. et al. Synapse formation: from cellular and molecular mechanisms to neurodevelopmental and neurodegenerative disorders. J. Neurophysiol. 121, 1381–1397 (2019).

    CAS  PubMed  Google Scholar 

  92. Miller, M. L. et al. Adolescent exposure to Delta(9)-tetrahydrocannabinol alters the transcriptional trajectory and dendritic architecture of prefrontal pyramidal neurons. Mol. Psychiatry 24, 588–600 (2019).

    CAS  PubMed  Google Scholar 

  93. Winterer, G. et al. Prefrontal broadband noise, working memory, and genetic risk for schizophrenia. Am. J. Psychiatry 161, 490–500 (2004).

    PubMed  Google Scholar 

  94. Winterer, G. & Weinberger, D. R. Genes, dopamine and cortical signal-to-noise ratio in schizophrenia. Trends Neurosci. 27, 683–690 (2004).

    CAS  PubMed  Google Scholar 

  95. Friedman, A. L., Meurice, C. & Jutkiewicz, E. M. Effects of adolescent Delta9-tetrahydrocannabinol exposure on the behavioral effects of cocaine in adult Sprague-Dawley rats. Exp. Clin. Psychopharmacol. 27, 326–337 (2019).

    CAS  PubMed  Google Scholar 

  96. Lecca, D. et al. Adolescent cannabis exposure increases heroin reinforcement in rats genetically vulnerable to addiction. Neuropharmacology 166, 107974 (2020).

    CAS  PubMed  Google Scholar 

  97. Stopponi, S. et al. Chronic THC during adolescence increases the vulnerability to stress-induced relapse to heroin seeking in adult rats. Eur. Neuropsychopharmacol. 24, 1037–1045 (2014).

    CAS  PubMed  Google Scholar 

  98. Tomasiewicz, H. C. et al. Proenkephalin mediates the enduring effects of adolescent cannabis exposure associated with adult opiate vulnerability. Biol. Psychiatry 72, 803–810 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Scherma, M. et al. Adolescent Delta(9)-tetrahydrocannabinol exposure alters WIN55,212-2 self-administration in adult rats. Neuropsychopharmacology 41, 1416–1426 (2016).

    CAS  PubMed  Google Scholar 

  100. Volkow, N. D., Wise, R. A. & Baler, R. The dopamine motive system: implications for drug and food addiction. Nat. Rev. Neurosci. 18, 741–752 (2017).

    CAS  PubMed  Google Scholar 

  101. Szutorisz, H., Egervari, G., Sperry, J., Carter, J. M. & Hurd, Y. L. Cross-generational THC exposure alters the developmental sensitivity of ventral and dorsal striatal gene expression in male and female offspring. Neurotoxicol. Teratol. 58, 107–114 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Szutorisz, H. & Hurd, Y. L. Epigenetic effects of cannabis exposure. Biol. Psychiatry 79, 586–594 (2016).

    CAS  PubMed  Google Scholar 

  103. Szutorisz, H. & Hurd, Y. L. High times for cannabis: Epigenetic imprint and its legacy on brain and behavior. Neurosci. Biobehav. Rev. https://doi.org/10.1016/j.neubiorev.2017.05.011 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Baedke, J. The epigenetic landscape in the course of time: Conrad Hal Waddington’s methodological impact on the life sciences. Stud. Hist. Philos. Biol. Biomed. Sci. 44, 756–773 (2013).

    PubMed  Google Scholar 

  105. Van Speybroeck, L. From epigenesis to epigenetics: the case of C. H. Waddington. Ann. N. Y. Acad. Sci. 981, 61–81 (2002).

    PubMed  Google Scholar 

  106. Dambacher, S., de Almeida, G. P. & Schotta, G. Dynamic changes of the epigenetic landscape during cellular differentiation. Epigenomics 5, 701–713 (2013).

    CAS  PubMed  Google Scholar 

  107. Dillon, N. Factor mediated gene priming in pluripotent stem cells sets the stage for lineage specification. Bioessays 34, 194–204 (2012).

    CAS  PubMed  Google Scholar 

  108. D’Addario, C., Di Francesco, A., Pucci, M., Finazzi Agro, A. & Maccarrone, M. Epigenetic mechanisms and endocannabinoid signalling. FEBS J. 280, 1905–1917 (2013).

    PubMed  Google Scholar 

  109. Meccariello, R. et al. The epigenetics of the endocannabinoid system. Int. J. Mol. Sci. 21, https://doi.org/10.3390/ijms21031113 (2020).

  110. Weaver, I. C. Integrating early life experience, gene expression, brain development, and emergent phenotypes: unraveling the thread of nature via nurture. Adv. Genet. 86, 277–307 (2014).

    CAS  PubMed  Google Scholar 

  111. Bayraktar, G. & Kreutz, M. R. Neuronal DNA methyltransferases: epigenetic mediators between synaptic activity and gene expression? Neuroscientist 24, 171–185 (2018).

    CAS  PubMed  Google Scholar 

  112. Morris, C. V., DiNieri, J. A., Szutorisz, H. & Hurd, Y. L. Molecular mechanisms of maternal cannabis and cigarette use on human neurodevelopment. Eur. J. Neurosci. 34, 1574–1583 (2011).

    PubMed  PubMed Central  Google Scholar 

  113. Volkow, N. D. & Morales, M. The brain on drugs: from reward to addiction. Cell 162, 712–725 (2015).

    CAS  PubMed  Google Scholar 

  114. Lim, D. A. et al. Chromatin remodelling factor Mll1 is essential for neurogenesis from postnatal neural stem cells. Nature 458, 529–533 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Scherma, M. et al. Cannabinoid exposure in rat adolescence reprograms the initial behavioral, molecular, and epigenetic response to cocaine. Proc. Natl Acad. Sci. USA 117, 9991–10002 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Tomas-Roig, J. et al. Chronic exposure to cannabinoids during adolescence causes long-lasting behavioral deficits in adult mice. Addict. Biol. 22, 1778–1789 (2017).

    CAS  PubMed  Google Scholar 

  117. Hollins, S. L., Zavitsanou, K., Walker, F. R. & Cairns, M. J. Alteration of imprinted Dlk1-Dio3 miRNA cluster expression in the entorhinal cortex induced by maternal immune activation and adolescent cannabinoid exposure. Transl. Psychiatry 4, e452 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Weaver, I. C. et al. Stress and the emerging roles of chromatin remodeling in signal integration and stable transmission of reversible phenotypes. Front. Behav. Neurosci. 11, 41 (2017).

    PubMed  PubMed Central  Google Scholar 

  119. Szutorisz, H. et al. Parental THC exposure leads to compulsive heroin-seeking and altered striatal synaptic plasticity in the subsequent generation. Neuropsychopharmacology 39, 1315–1323 (2014). This study is the first to demonstrate that preconception exposure to THC affects neurobehavioural and neurophysiological phenotypes in the offspring.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Watson, C. T. et al. Genome-wide DNA methylation profiling reveals epigenetic changes in the rat nucleus accumbens associated with cross-generational effects of adolescent THC exposure. Neuropsychopharmacology 40, 2993–3005 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. de Bartolomeis, A. & Tomasetti, C. Calcium-dependent networks in dopamine-glutamate interaction: the role of postsynaptic scaffolding proteins. Mol. Neurobiol. 46, 275–296 (2012).

    CAS  PubMed  Google Scholar 

  122. Wang, Z., Yan, P., Hui, T. & Zhang, J. Epigenetic upregulation of PSD-95 contributes to the rewarding behavior by morphine conditioning. Eur. J. Pharmacol. 732, 123–129 (2014).

    CAS  PubMed  Google Scholar 

  123. Spiers, H. et al. Methylomic trajectories across human fetal brain development. Genome Res. 25, 338–352 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Wilson, M. E. & Sengoku, T. Developmental regulation of neuronal genes by DNA methylation: environmental influences. Int. J. Dev. Neurosci. 31, 448–451 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Hempel, B. J. et al. Cross-generational THC exposure alters heroin reinforcement in adult male offspring. Drug. Alcohol. Depend. 212, 107985 (2020).

    CAS  PubMed  Google Scholar 

  126. Pitsilis, G., Spyridakos, D., Nomikos, G. G. & Panagis, G. Adolescent female cannabinoid exposure diminishes the reward-facilitating effects of Delta9-tetrahydrocannabinol and d-amphetamine in the adult male offspring. Front. Pharmacol. 8, 225 (2017).

    PubMed  PubMed Central  Google Scholar 

  127. Vassoler, F. M., Johnson, N. L. & Byrnes, E. M. Female adolescent exposure to cannabinoids causes transgenerational effects on morphine sensitization in female offspring in the absence of in utero exposure. J. Psychopharmacol. 27, 1015–1022 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Byrnes, J. J., Johnson, N. L., Schenk, M. E. & Byrnes, E. M. Cannabinoid exposure in adolescent female rats induces transgenerational effects on morphine conditioned place preference in male offspring. J. Psychopharmacol. 26, 1348–1354 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Holloway, Z. R. et al. Paternal factors in neurodevelopmental toxicology: THC exposure of male rats causes long-lasting neurobehavioral effects in their offspring. Neurotoxicology 78, 57–63 (2020).

    CAS  PubMed  Google Scholar 

  130. Levin, E. D. et al. Paternal THC exposure in rats causes long-lasting neurobehavioral effects in the offspring. Neurotoxicol. Teratol. 74, 106806 (2019).

    CAS  PubMed  Google Scholar 

  131. Yang, Q. et al. Highly sensitive sequencing reveals dynamic modifications and activities of small RNAs in mouse oocytes and early embryos. Sci. Adv. 2, e1501482 (2016).

    PubMed  PubMed Central  Google Scholar 

  132. Morris, A. The endocannabinoid system in human testes. Nat. Rev. Endocrinol. 15, 684–685 (2019).

    CAS  PubMed  Google Scholar 

  133. Walker, O. S., Holloway, A. C. & Raha, S. The role of the endocannabinoid system in female reproductive tissues. J. Ovarian Res. 12, 3 (2019).

    PubMed  PubMed Central  Google Scholar 

  134. Klonoff-Cohen, H. S., Natarajan, L. & Chen, R. V. A prospective study of the effects of female and male marijuana use on in vitro fertilization (IVF) and gamete intrafallopian transfer (GIFT) outcomes. Am. J. Obstet. Gynecol. 194, 369–376 (2006).

    CAS  PubMed  Google Scholar 

  135. Banerjee, A., Singh, A., Srivastava, P., Turner, H. & Krishna, A. Effects of chronic bhang (cannabis) administration on the reproductive system of male mice. Birth Defects Res. B Dev. Reprod. Toxicol. 92, 195–205 (2011).

    CAS  PubMed  Google Scholar 

  136. Maccarrone, M., Rapino, C., Francavilla, F. & Barbonetti, A. Cannabinoid signalling and effects of cannabis on the male reproductive system. Nat. Rev. Urol. 18, 19–32 (2021).

    CAS  PubMed  Google Scholar 

  137. Payne, K. S., Mazur, D. J., Hotaling, J. M. & Pastuszak, A. W. Cannabis and male fertility: a systematic review. J. Urol. 202, 674–681 (2019).

    PubMed  PubMed Central  Google Scholar 

  138. Murphy, S. K. et al. Cannabinoid exposure and altered DNA methylation in rat and human sperm. Epigenetics https://doi.org/10.1080/15592294.2018.1554521 (2018). This is the first study to demonstrate the effects of THC/cannabis on DNA methylation in human sperm.

    Article  PubMed  PubMed Central  Google Scholar 

  139. Schrott, R. et al. Cannabis use is associated with potentially heritable widespread changes in autism candidate gene DLGAP2 DNA methylation in sperm. Epigenetics 15, 161–173 (2020).

    PubMed  Google Scholar 

  140. Gapp, K. et al. Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat. Neurosci. 17, 667–669 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Rodgers, A. B. & Bale, T. L. Germ cell origins of posttraumatic stress disorder risk: the transgenerational impact of parental stress experience. Biol. Psychiatry 78, 307–314 (2015).

    PubMed  PubMed Central  Google Scholar 

  142. Gapp, K. et al. Alterations in sperm long RNA contribute to the epigenetic inheritance of the effects of postnatal trauma. Mol. Psychiatry https://doi.org/10.1038/s41380-018-0271-6 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Grandjean, V. et al. RNA-mediated paternal heredity of diet-induced obesity and metabolic disorders. Sci. Rep. 5, 18193 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Chen, Q. et al. Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder. Science 351, 397–400 (2016).

    CAS  PubMed  Google Scholar 

  145. Benito, E. et al. RNA-dependent intergenerational inheritance of enhanced synaptic plasticity after environmental enrichment. Cell Rep. 23, 546–554 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Jung, Y. H. et al. Chromatin states in mouse sperm correlate with embryonic and adult regulatory landscapes. Cell Rep. 18, 1366–1382 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Tomas-Roig, J. et al. Chronic exposure to cannabinoids during adolescence causes long-lasting behavioral deficits in adult mice. Addict. Biol. https://doi.org/10.1111/adb.12446 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Ibn Lahmar Andaloussi, Z., Taghzouti, K. & Abboussi, O. Behavioural and epigenetic effects of paternal exposure to cannabinoids during adolescence on offspring vulnerability to stress. Int. J. Dev. Neurosci. 72, 48–54 (2019).

    CAS  PubMed  Google Scholar 

  149. Rodríguez de Fonseca, F., Ramos, J. A., Bonnin, A. & Fernández-Ruiz, J. J. Presence of cannabinoid binding sites in the brain from early postnatal ages. Neuroreport 4, 135–138 (1993).

    PubMed  Google Scholar 

  150. Glass, M., Dragunow, M. & Faull, R. L. Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience 77, 299–318 (1997). This is a seminal early study showing the expression of CB1R in the human brain in different developmental periods and in adulthood.

    CAS  PubMed  Google Scholar 

  151. Long, L. E., Lind, J., Webster, M. & Weickert, C. S. Developmental trajectory of the endocannabinoid system in human dorsolateral prefrontal cortex. BMC Neurosci. 13, 87 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Zias, J. et al. Early medical use of cannabis. Nature 363, 215 (1993).

    CAS  PubMed  Google Scholar 

  153. Mechoulam, R. & Hanus, L. A historical overview of chemical research on cannabinoids. Chem. Phys. Lipids 108, 1–13 (2000).

    CAS  PubMed  Google Scholar 

  154. ElSohly, M. A., Radwan, M. M., Gul, W., Chandra, S. & Galal, A. Phytochemistry of Cannabis sativa L. Prog. Chem. Org. Nat. Prod. 103, 1–36 (2017).

    CAS  PubMed  Google Scholar 

  155. ElSohly, M. A. et al. Potency trends of delta9-THC and other cannabinoids in confiscated marijuana from 1980–1997. J. Forensic Sci. 45, 24–30 (2000).

    CAS  PubMed  Google Scholar 

  156. Chandra, S. et al. New trends in cannabis potency in USA and Europe during the last decade (2008–2017). Eur. Arch. Psychiatry Clin. Neurosci. https://doi.org/10.1007/s00406-019-00983-5 (2019).

    Article  PubMed  Google Scholar 

  157. Raber, J. C., Elzinga, S. & Kaplan, C. Understanding dabs: contamination concerns of cannabis concentrates and cannabinoid transfer during the act of dabbing. J. Toxicol. Sci. 40, 797–803 (2015).

    PubMed  Google Scholar 

  158. Stogner, J. M. & Miller, B. L. Assessing the dangers of “dabbing”: mere marijuana or harmful new trend? Pediatrics 136, 1–3 (2015).

    PubMed  Google Scholar 

  159. Armstrong, M. J., Jin, Y., Allen, E. G. & Jin, P. Diverse and dynamic DNA modifications in brain and diseases. Hum. Mol. Genet. 28, R241–R253 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Greenberg, M. V. C. & Bourc’his, D. The diverse roles of DNA methylation in mammalian development and disease. Nat. Rev. Mol. Cell Biol. 20, 590–607 (2019).

    CAS  PubMed  Google Scholar 

  161. Bhaumik, S. R., Smith, E. & Shilatifard, A. Covalent modifications of histones during development and disease pathogenesis. Nat. Struct. Mol. Biol. 14, 1008–1016 (2007).

    CAS  PubMed  Google Scholar 

  162. Chan, J. C. & Maze, I. Nothing is yet set in (hi)stone: novel post-translational modifications regulating chromatin function. Trends Biochem. Sci. 45, 829–844 (2020).

    PubMed  PubMed Central  Google Scholar 

  163. Iyengar, B. R. et al. Non-coding RNA interact to regulate neuronal development and function. Front. Cell. Neurosci. 8, 47 (2014).

    PubMed  PubMed Central  Google Scholar 

  164. Yoshino, Y. & Dwivedi, Y. Non-coding RNAs in psychiatric disorders and suicidal behavior. Front. Psychiatry 11, 543893 (2020).

    PubMed  PubMed Central  Google Scholar 

  165. Legoff, L., D’Cruz, S. C., Tevosian, S., Primig, M. & Smagulova, F. Transgenerational inheritance of environmentally induced epigenetic alterations during mammalian development. Cells https://doi.org/10.3390/cells8121559 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors were supported by NIDA grants DA030359 and DA050403 (G.R.).

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Authors and Affiliations

  1. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, Mount Sinai, NY, USA

    Anissa Bara, Jacqueline-Marie N. Ferland, Gregory Rompala, Henrietta Szutorisz & Yasmin L. Hurd

  2. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, Mount Sinai, NY, USA

    Anissa Bara, Jacqueline-Marie N. Ferland, Gregory Rompala, Henrietta Szutorisz & Yasmin L. Hurd

  3. Addiction Institute of Mount Sinai, Mount Sinai, NY, USA

    Anissa Bara, Jacqueline-Marie N. Ferland, Gregory Rompala, Henrietta Szutorisz & Yasmin L. Hurd

  4. Friedman Brain Institute, Mount Sinai, NY, USA

    Anissa Bara, Jacqueline-Marie N. Ferland, Gregory Rompala, Henrietta Szutorisz & Yasmin L. Hurd

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Bara, A., Ferland, JM.N., Rompala, G. et al. Cannabis and synaptic reprogramming of the developing brain. Nat Rev Neurosci 22, 423–438 (2021). https://doi.org/10.1038/s41583-021-00465-5

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