Cannabis and synaptic reprogramming of the developing brain

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.

Fig. 1 |. Neurodevelopmental pattern of the endocannabinoid system in humans and rodents.

Top panel: Schematic overview of the developmental pattern of the expression of cannabinoid receptor type 1 (CB₁R), endocannabinoid (eCB) ligands (2-arachidonyolglycerol (2-AG) and anandamide (AEA)), synthesis enzymes (diacylglycerol lipase (DAGL) and N-acylphosphatidylethanolamine-selective phospholipase D (NAPE-PLD)) and degradative enzymes (monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH)) detected in the brain (single asterisk, human; two asterisks, rodent; three asterisks, human and rodent). In rodents, the Cnr1 gene, encoding CB₁R, exhibits its highest expression during early development and then expression decreases until adulthood. Consistently, CB₁R binding progressively increases from early gestation to reach maximal densities during adolescence in various brain regions (striatum, limbic forebrain and ventral mesencephalon) before decreasing to sustained high levels in the adult brain. In humans, CB₁R appears to have a similar developmental pattern from mid-to-late gestation to adulthood in homologous brain areas with an extremely high density in adulthood^,,. The eCB ligands also have distinct ontogenic patterns. While AEA expression exhibits a progressive increase from late gestation in rodents to reach maximal levels during adolescence, 2-AG expression peaks just after birth and fluctuates in early and late adole scence before reaching its adult levels^,,. In rodents, the AEA-synthesizing enzyme NAPE-PLD is first expressed in late gestation, and human studies show that NAPE-PLD mRNA expression in the prefrontal cortex increases steadily over the lifespan, while expression of FAAH, the enzyme that degrades AEA, peaks during adolescence before maintaining stable levels into adulthood. The ontogenic presence of 2-AG requires active DAGL and MAGL. While the expression profiles throughout development for MAGL and DAGL have not been well studied in rodents, the human prefrontal cortex exhibits a progressive increase of DAGL mRNA levels until early adulthood, whereas MAGL expression reaches its peak in early childhood before to declining in early adulthood. Bottom panel: Illustration of several neurodevelopment events which occur from gestation to early adulthood that are regulated by eCB signalling (see the top panel). The gestation period is characterized by neuronal generation and migration followed in a later stage by synaptogenesis and synaptic transmission that continues into infancy, childhood and adulthood. The adolescent period is characterized by synaptic pruning (elimination of synapses) that shapes the mature brain architecture with dynamic fluctuations of components of the eCB system, including CB₁R expression, eCB ligands and FAAH activity during early and late adolescence.

Fig. 2 |. Impact of developmental THC exposure on synaptic plasticity in adulthood.

Schematic overview of the synapse under normal conditions or after perinatal or adolescent Δ⁹-tetrahydrocannabinol (THC) exposure based on rodent models. a | During normal conditions, in the absence of THC exposure, endocannabinoid (eCBs) synthesized postsynaptically are released into the synaptic cleft and influence GABAergic and glutamatergic synapses by binding to cannabinoid receptor type 1 (CB₁R) expressed presynaptically. In this way, the eCB system tightly regulates these synapses as well as other neurotransmitter systems such as the dopamine system (for example, indirectly regulated by cannabinoid receptor on inhibitory GABA terminals that synapse onto dopaminergic neurons; not shown in figure). b | After prenatal THC exposure, GABAergic mechanisms are significantly abrogated due to a decrease in voltage-sensitive calcium channel (VSCC) density, synaptic ‘crowding’ by bassoon scaffolding proteins and reduced GABA release. In contrast, glutamatergic and dopaminergic inputs are sensitized (as measured by increased firing and excitability), which is paired with shifts in postsynaptic receptor expression, including reduced dopamine D₂ receptor (D₂R) and metabotropic glutamate receptor 5 (mGlu5) levels and increased AMPA/NMDA ratios, hallmarks of compensatory downregulation. Moreover, prenatal THC exposure impacts the expression of eCB system enzymes (increased monoacylglycerol lipase (MAGL) and decreased diacylglycerol lipase (DAGL) expression), resulting in a reduction of eCB bioavailability (represented by the red triangles). c | Similarly, adolescent THC exposure results in significant reductions in GABAergic tone via reductions in the expression of the critical GABA synthesis enzyme glutamate decarboxylase 67 (GAD67) as well as greater firing and excitability of presynaptic glutamatergic neurons and dopaminergic inputs. In the postsynaptic cell, expression of AMPA and NMDA receptors is increased in animals with adolescent THC exposure. Although the same biological markers are not always studied in perinatal and adolescent models, adolescent THC exposure also alters the architecture of the synapse, as evident in increased expression of postsynaptic density protein 95 (PSD95) at glutamatergic synapses. In addition, adolescent THC exposure leads to disruptions of key eCB system components, including reduced expression of CB₁Rs, impaired CB₁R G protein functionality (as depicted by red crosses) associated with increased expression of second messengers such as adenyl cyclase (AC) and cyclic adenosine monophosphate (cAMP) and abnormal levels of anandamide (AEA). AMPAR, AMPA receptor; NMDAR, NMDA receptor.

Fig. 3 |. Overview of proposed epigenetic effects induced by exogenous cannabinoids on the developing brain and epigenetic reprogramming of the germ line.

Epigenetic mechanisms, which occur on DNA in the nucleus of cells to regulate gene expression, are sensitive to cannabinoid exposure. During perinatal and adolescent stages of development, the chromatin structure of gene loci functionally related to synaptic plasticity (depicted by the synapse) is in a more open state, regulated by epigenetic and transcriptional machinery (represented by various coloured shapes) that can be altered by external stimuli such as cannabinoid exposure. As development progresses, this higher sensitivity of epigenetic responsiveness declines, rendering the adult brain less vulnerable to external influences. Marked epigenetic remodelling occurs during germ cell production, and reprogrammed germ cells are sensitive to the effects of cannabis. Such epigenetic interference by cannabis may escape the normal reprogramming of the germ line and thereby lead to intergenerational transmission, affecting the offspring from the earliest stages of development. The exact epigenetic mechanisms contributing to intergenerational transmission remain to be elucidated.