Exposure of adolescents to delta-9-tetrahydrocannabinol (THC), the main psychoactive component in cannabis, may lead to disturbances in neuronal structure and gene expression in the prefrontal cortex (PFC) in adulthood, new research suggests.
Using cell type– and layer-specific high-resolution microscopy, dissection aided by laser capture, and next-generation RNA sequencing, investigators examined the impact of THC on the neurodevelopment of exposed adolescent rats through a comparison with control rats.
They found that adolescent THC exposure reduced the branching of prefrontal cortical neurons and the number of spines, which are essential for cellular communication.
Moreover, THC altered the associated genes that regulate the development of neurons. This was accompanied by significant changes in genes related to epigenetic mechanisms.
The alterations in gene-expression neurons were similar to disturbances in these networks found in individuals with schizophrenia.
"Adolescent THC exposure can have a long-term impact on the structure of cortical neurons and associated genes that regulate the development of neurons and changes the sensitivity of gene networks relevant to psychosis risk," senior author Yasmin Hurd, PhD, director, the Addiction Institute of Mount Sinai, Icahn School of Medicine at Mount Sinai, New York City, told Medscape Medical News.
"[It is] important to emphasize the negative impact of marijuana use, particularly in teens with psychosis risk," she said.
The study was published online October 3 in Molecular Psychiatry.
Novel Approach
Cannabis is widely used by adolescents, which is concerning because exposure to exogenous cannabinoids "is linked to changes in adult neurobiology and behavior relevant to psychiatric disease, specifically psychotic disorders such as schizophrenia," the authors write.
The psychoactive effects of cannabis occur when THC binds to the cannabinoid 1 receptor (CB1R), a central component of the endocannabinoid (eCB) system, and disturbances of CB1R signaling in the PFC are implicated in schizophrenia, they explain.
The PFC continues to develop throughout adolescence. Dynamic fluctuations in components of the eCB system occur throughout adolescent development and play a role in neuronal development and synaptic plasticity.
Because this controlled regulation relates to the fine-tuning of PFC circuits established during adolescence, cannabis exposure during that critical period "likely induces long-term consequences by interfering with the architecture of PFC neurocircuitry," the authors suggest.
Human neuroimaging studies demonstrate that in individuals who have a history of adolescent cannabis use, PFC volume and function are altered, "but the cellular and molecular phenotype of such disturbances remains unknown," the authors note.
To study the impact of THC on the developing adolescent brain, the researchers used a rat model, because the prelimbic (PrL) subregion of the rodent ventromedial PFC — in particular, layer III — mediates cognitive and decision-making functions as well as emotional regulation.
Pyramidal neurons in the PrL "exhibit the most pronounced developmental pruning and the highest rate of spine turnover of PFC subdivisions during adolescence," the authors state.
Moreover, disruption of the PrL is implicated in the etiology of schizophrenia.
Knowledge of the molecular phenotype of these cells and the long-term impact of THC exposure on their molecular development is lacking.
The researchers developed a "novel multidisciplinary approach" in which laser capture microdissection was used to isolate mRNA from discrete cortical cellular populations in a region- and layer-specific manner appropriate for next-generation sequencing with low RNA input.
The purpose was to "directly measure the dendritic structure and molecular phenotype of layer III PrL pyramidal neurons in a rodent model of adolescent THC exposure," they write.
THC-treated rats were compared with a group of control rats that had been treated with vehicle (VEH) containing a non-THC solution.
Both groups of rats were injected with THC or VEH beginning on postnatal day 28 and continuing every third day for a total of eight injections.
The brains and blood were collected 24 hours or 2 weeks after the final injection.
Morphologic Correlate
The researchers reconstructed the apical and basal dendritic trees of layer III PrL pyramidal neurons and found that arbor development was "markedly reorganized" by THC exposure, with altered dendritic arbor complexity.
Throughout development, the VEH-treated rats exhibited stable apical trees, but the complexity of basal trees was expanded into adulthood.
By contrast, the THC-treated rats differed significantly. The treatment increased arborization in distal apical and basal trees 24 hours after the last injection.
However, in early adulthood, 2 weeks after drug exposure, the THC-treated animals showed significant atrophy in distal apical arbors.
Only the THC-treated rats exhibited a reduction in basal tree complexity from adolescence to adulthood, "emphasizing the marked reorganization of arbor development induced by drug exposure," the authors comment.
Additionally, adolescent THC exposure was found to prematurely prune dendritic spines, which are found on arbor branches and are "a central morphological feature of synaptic plasticity involved in the maturation of the cortex and implicated in the pathophysiology of neuropsychiatric disorders," the investigators state.
The pruning of these spines that normally takes place between adolescence and adulthood and that was found in the VEH-treated rats was absent in the THC-treated rats as early as 24 hours after the last injection.
"These findings suggest a morphological correlate of adolescent THC-mediated alterations of PFC structure observed in humans," the authors write.
Protracted Effects
The researchers then used next-generation RNA sequencing to measure the transcriptome of morphologically distinct layer III cellular populations.
After confirming that this approach succeeded in selectively isolating and sequencing morphologically defined PrL cellular populations, they "interrogated the transcriptomic profile of layer III PrL pyramidal neurons in the rat adolescent THC model."
In evaluating the genes at adolescent and young adult time points, the researchers identified genes associated with the early and protracted effects of THC, respectively.
They found that 698 (5.6%) of 12,568 genes that they investigated were differentially expressed in THC-treated animals 24 hours after their last injection compared to control animals.
Two weeks after the last injection, 608 of differentially expressed genes (4.8%) were identified in THC-treated animals, compared with control animals.
THC had "protracted effects" on gene networks that are associated with microtubule organization and cytochrome complex assembly, the authors note.
Similar to Schizophrenia
The researchers then addressed a key question: Would TCH exposure affect the transcriptional ontogeny of PrL neurons?
They found that 975 genes (7.8%) in the adult animals that had been treated with THC during adolescence were significantly different in young adulthood, compared to 797 (6.3%) in the VEH-treated animals.
Genes dysregulated by developmental THC "uniquely disrupted epigenetic mechanisms" by changing genes associated with actin cytoskeleton and dendritic regulation, as well as chromatin modification and histone methylation.
"This strategy revealed unique long-term morphological and transcriptomic aberrations during development associated with adolescent THC exposure," the writers summarize.
In light of the relationship between cannabis use, PFC development, and schizophrenia, the researchers evaluated the relationship between genes dysregulated by developmental THC and human schizophrenia.
They found that dysregulated PFC coexpression networks, which were common to THC-treated rats and patients with schizophrenia, were "enriched for cytoskeletal and neurite development."
"The results demonstrate that adolescent exposure to THC alters the developmental trajectory into adulthood of prefrontal cortical neurons, which are critical for decision making and cognitive function," Hurd commented.
"The impairments were evident in the structure of neurons, where there was reduced complicity of the neurons critical for communication between cells," she continued.
"The impairments were also evident in the expression of genes critical for synaptic plasticity and epigenetic mechanisms that regulate DNA openness and chromatin structure that determines whether genes are turned on or off," she said.
Moreover, "the gene network alterations were similar to those observed to be impaired in the PRC of people with schizophrenia," she added.
Potent Concentrations
Commenting on the study for Medscape Medical News, Tiziana Rubino, PhD, Department of Biotechnology and Life Sciences and Neuroscience Center, University of Insubria, Italy, who was not involved with the study, said that the researchers "once again published a remarkable work on the possible consequences of cannabis exposure during adolescence."
She suggested that the "ongoing debate on cannabis policy needs to take into account this scientifically based evidence in order to prevent the possible harmful consequences of early and/or heavy cannabis consumption in adolescence."
Also commenting on the study for Medscape Medical News, Steven Laviolette, PhD, associate professor, Schulich School of Medicine and Dentistry, University of Western Ontario, Canada, who was not involved with the research, called it "a very elegant study" with "important implications for understanding why adolescent exposure to marijuana, especially strains of marijuana with high levels of THC, can lead to increased vulnerability to psychiatric disorders such as schizophrenia in later life."
Hurd added, "Future studies will determine whether other cannabinoids such as cannabidiol that are devoid of psychoactive properties also induce similar alterations or can counter the effects induced by THC."
Moreover, "it is important to investigate the effects of high THC doses, considering that marijuana being used recreationally today [can] have very potent concentrations of THC," she said.
The research was supported by the National Institute on Drug Abuse, the National Institute on Aging, the National Institute of Mental Health, and the National Institute of General Medical Sciences. Dr Hurd, the study authors, Dr Rubino, and Dr Laviolette have disclosed no relevant financial relationships.
Mol Psychiatry. Published online October 3, 2018. Full text
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Cite this: Teen Cannabis Use May Increase Adult Psychosis Risk - Medscape - Oct 30, 2018.
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