Cannabis and synaptic reprogramming of the developing brain

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

Nature Reviews | Neuroscience, 2021,

https://doi.org/10.1038/s41583-021-00465-5

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.

 

There has been a large societal shift in recent years in the perception of harm from cannabis use coinciding with its widespread legalization for recreational and/or medicinal use in most states in the USA and many countries worldwide. Despite important societal outcomes of these changes, such as the decriminalization of cannabis use, the potential for harm particularly for vulnerable populations has raised concern as more teens and pregnant women use cannabis today. This is also pertinent given the exponential increase over the years in the concentration of Δ9- tetrahydrocannabinol (THC; the main psychoactive intoxicant) in the cannabis used recreationally and sold in dispensaries (Box 1). Brain development is a dynamic process that extends well beyond the prenatal period, where full maturity is not achieved until early adulthood. The endocannabinoid (eCB) system (ECS) (Box 1), which mediates the actions of THC, plays a critical regulatory role throughout all developmental stages, from the determination of cell fate and neuronal migration to the regulation of signalling pathways and synaptic transmission in the mature central nervous system (CNS). Therefore, the supraphysiological impact on
the ECS by cannabis exposure during critical periods of development could change the normal trajectory of cellular processing and neurocircuitry, leading to behavioural disturbances later in life. In this Review, we provide a general overview of the ECS (which has been extensively reviewed) and describe the neurodevelopmental effects of cannabis/THC on the basis of animal and human studies relevant to neuropsychiatric risk.

While evident discrepancies exist in the literature and not all studies observe adverse cannabis outcomes, we focus on animal findings pertinent to human cannabis studies reporting neurobehavioural disorders in order to gain neurobiological insights germane to risk. We highlight epigenetic mechanisms as a critical link underlying the molecular processes that maintain protracted effects of developmental cannabis exposure, not just during one’s lifetime but across generations.

The endocannabinoid system

The ECS plays a broad and critical role in numerous developmental processes. Briefly, it consists of cannabinoid receptors (CBRs; CB1R and CB2R) and endogenous ligands (eCBs), including the most studied 2- arachidonoylglycerol (2- AG) and anandamide (AEA), as well as the proteins responsible for their transport, synthesis (diacylglycerol lipase (DAGL) and N- acylphosphatidylethanolamine- selective phospholipase D (NAPE- PLD)) and degradation (monoacylglycerollipase (MAGL) and fatty acid amide hydrolase (FAAH)). eCBs, which are lipidic neuromodulators, can interact with other receptors, including transient receptor potential vanilloid 1 (TRPV1), peroxisome proliferator- activated receptor (PPAR) and G- protein- coupled receptor 55 (GPR55), to regulate synaptic transmission (for a review, see ref.1).

A substantial literature highlights fundamental roles of eCBs and CBRs in key developmental processes, including neurogenesis, glial formation, neuronal migration, axonal elongation, fasciculation (axonal bundling), synaptogenesis and synaptic pruning2–4.

While considerable gaps in knowledge remain regarding granular mechanisms by which the ECS regulates some of these processes, significant insights have been gained into specific expression patterns linked to the functional and structural maturation of the CNS (Fig. 1) relevant to cannabis exposure during these periods.

CB1R and CB2R are the primary targets of THC, with CB1R having a prominent role in CNS development
given its abundant expression in the developing brain in contrast to CB2R, the role of which is aligned mainly with cells of microglial/macrophage lineage5,6. CB1Rs are present and functional from at least the ninth gestational week in humans, a period that overlaps with the initiation of cortical development, and from gestational day 11 in rodents5–7. In both rodents and humans, there is a transient presence of CB1Rs on white matter neuronal fibres during embryonic stages8–10, potentially reflecting CB1R on axons as they grow and migrate to their final site in establishing neuronal pathways, or their presence
on non- neuronal cells (astrocytes and oligodendrocytes) that guide neuronal migration and axonal elongation. CB1R, expressed by diverse pluripotent cells, regulates cell differentiation and proliferation3,11, with expression correlated with neural differentiation12. Rodent studies have clearly demonstrated that CB1R expression and eCB signalling in postmitotic neurons play critical roles in neuronal migration and differentiation of glutamate and GABAergic cortical cells, cholinergic basal forebrain neurons, GABAergic cerebellar cells and hypothalamic neurons13. Moreover, the expression of CB1R by progenitor cells can control the neuron- to- glia ratio in the brain, and alterations in CB1R expression during fetal development can modify the connectivity between brain regions such as the cerebral cortex and hippocampus2,3. The developmental expression of CB1R is dynamic postnatally into adolescence before high levels are established in early adulthood, where CB1R is ubiquitously expressed and becomes the most abundant G- protein- coupled receptor14–16. CB1Rs in adulthood are primarily enriched in the cerebral cortex, basal ganglia, hippocampus and cerebellum14 and are predominantly
localized to the synapse on presynaptic terminals17 of both glutamatergic and GABAergic cells18.

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