, research in mice and humans suggested.
The multilevel study demonstrated that tetrahydrocannabinol (THC), an active substance in cannabis, causes shrinkage of dendritic arborization — the neurons’ network of antennae that play a critical role in communication between brain cells.
The connection between dendritic arborization and cortical thickness was hinted at in an earlier study by Tomáš Paus, MD, PhD, professor of psychiatry and addictology at the University of Montreal, Quebec, Canada, and colleagues, who found that cannabis use in early adolescence was associated with lower cortical thickness in boys with a high genetic risk for schizophrenia.
“We speculated at that time that the differences in cortical thickness might be related to differences in dendritic arborization, and our current study confirmed it,” Paus said.
That confirmation came in the mouse part of the study, when coauthor Graciela Piñeyro, MD, PhD, also of the University of Montreal, counted the dendritic branches of mice exposed to THC and compared the total with the number of dendritic branches in unexposed mice. “What surprised me was finding that THC in the mice was targeting the same type of cells and structures that Dr. Paus had predicted would be affected from the human studies,” she said. “Structurally, they were mostly the neurons that contribute to synapses in the cortex, and their branching was reduced.”
Paus explained that in humans, a decrease in input from the affected dendrites “makes it harder for the brain to learn new things, interact with people, cope with new situations, et cetera. In other words, it makes the brain more vulnerable to everything that can happen in a young person’s life.”
The study was published online on October 9 in the Journal of Neuroscience.
Of Mice, Men, and Cannabis
Although associations between cannabis use by teenagers and variations in brain maturation have been well studied, the cellular and molecular underpinnings of these associations were unclear, according to the authors.
To investigate further, they conducted this three-step study. First, they exposed adolescent male mice to THC or a synthetic cannabinoid (WIN 55,212-2) and assessed differentially expressed genes, spine numbers, and the extent of dendritic complexity in the frontal cortex of each mouse.
Next, using MRI, they examined differences in cortical thickness in 34 brain regions in 140 male adolescents who experimented with cannabis before age 16 years and 327 who did not.
Then, they again conducted experiments in mice and found that 13 THC-related genes correlated with variations in cortical thickness. Virtual histology revealed that these 13 genes were coexpressed with cell markers of astrocytes, microglia, and a type of pyramidal cell enriched in genes that regulate dendritic expression.
Similarly, the WIN-related genes correlated with differences in cortical thickness and showed coexpression patterns with the same three cell types.
Furthermore, the affected genes were also found in humans, particularly in the thinner cortical regions of the adolescents who experimented with cannabis.
By acting on microglia, THC seems to promote the removal of synapses and, eventually, the reduction of the dendritic tree in mice, Piñeyro explained. That’s important not only because a similar mechanism may be at work in humans but also because “we now might have a model to test different types of cannabis products to see which ones are producing the greatest effect on neurons and therefore greater removal of synapses through the microglia. This could be a way of testing drugs that are out in the street to see which would be the most or least dangerous to the synapses in the brain.”