Scientists have discovered that a specific type of brain cell, called an astrocyte, may be a key player in how cannabis influences the developing brain. Their new research in mice, published in iScience, reveals that cannabinoid receptors located on astrocytes are essential for the brain’s ability to adapt and change early in life, a process known as plasticity. When these receptors were removed from astrocytes, the young mice’s visual systems struggled to adjust to changes in their environment, suggesting that astrocytes and their cannabinoid receptors are unexpectedly important for brain development.
Cannabis is known to bind to cannabinoid receptors in the brain, and these receptors are involved in numerous brain functions. For a long time, it was generally thought that these receptors primarily resided on nerve cells, which are the brain’s main communication units. However, recent evidence suggested that other types of brain cells, specifically astrocytes, might also possess these receptors and play a significant role.
Astrocytes are a type of support cell in the brain, known as glial cells. They have various support functions, helping nerve cells to function properly. Scientists knew from earlier research that astrocytes could influence brain plasticity. In a previous experiment, transplanting astrocytes from young cats into the visual cortex of older cats surprisingly made the older cats’ brains more adaptable again, reopening a period of heightened plasticity that typically exists only in young brains. This suggested that astrocytes held a key to brain flexibility.
It was also observed that the cannabinoid receptors on astrocytes become less active as we age, raising the question of whether these receptors on astrocytes are connected to the brain’s enhanced plasticity during youth. The current research team aimed to investigate this potential link and determine the precise role of cannabinoid receptors on astrocytes in brain development and plasticity. They wanted to understand if these receptors were indeed important for the brain’s ability to adjust and change during critical periods of development, and if so, how this might relate to the effects of cannabis, especially given concerns about cannabis use during adolescence when the brain is still maturing.
“The cannabinoid CB1 receptor is one of the most abundant signaling receptors in the brain. Our earlier work had shown that it is not only present on neurons, but also on supportive brain cells called astrocytes. In this study ,we wanted to investigate how these receptors on astrocytes contribute to brain plasticity,” said study author Rogier Min, a neuroscientist affiliated with the Amsterdam Leukodystrophy Center at the Amsterdam University Medical Center.
“In earlier studies from the 80s, researchers injected astrocytes from a kitten into the visual cortex of an older cat, the brain area involved in vision. As a result, the critical period was opened once more, meaning that the brain could adjust more easily again,” added Christiaan Levelt of the Netherlands Institute for Neuroscience. “We also know that the CB1-receptor in astrocytes is expressed less and less as we age. Could there be a link here? And could this mean that the CB1-receptor on astrocytes play a role in this critical period plasticity?”
To investigate this, the scientists used genetically modified mice. They created special mouse models in which they could selectively turn off cannabinoid receptors in specific types of brain cells. They created two groups of mice: in one group, the cannabinoid receptors were turned off only in nerve cells, and in the other group, they were turned off only in astrocytes. This allowed the researchers to examine the unique contribution of cannabinoid receptors in each of these cell types separately.
The researchers focused their study on the visual system, specifically the visual cortex, which is the area of the brain that processes visual information. They chose to study the visual system because it is a well-understood model for brain development and plasticity. A key aspect of brain development is plasticity, the brain’s ability to reorganize itself by forming new connections throughout life. This plasticity is particularly strong during specific windows of time in early development, known as critical periods.
During these critical periods, the brain is highly sensitive to experience and can readily adapt to its environment. One way to study plasticity in the visual system is through a process called monocular deprivation. This involves temporarily covering one eye during the critical period for vision. In normal young animals, the brain responds to this by strengthening the connections to the uncovered eye and weakening the connections to the covered eye, demonstrating the brain’s adaptability.
In their experiment, the researchers temporarily covered one eye of young mice during the critical period for visual development. They then examined how the brains of these mice adapted to this change, comparing the mice with cannabinoid receptors removed from nerve cells, those with receptors removed from astrocytes, and normal control mice. To assess the brain’s adaptability, they measured a process called ocular dominance plasticity. This refers to the shift in brain activity towards the eye that is receiving more visual input.
To understand the underlying mechanisms, the scientists also examined the development of inhibitory nerve cells in the brain. Inhibitory nerve cells, also known as interneurons, are essential for maintaining balance in brain activity. They act like brakes, preventing the brain from becoming overactive. The researchers studied how removing cannabinoid receptors from different cell types affected the development of these inhibitory cells and their connections in the visual cortex.
They used a technique called electrophysiology to measure the activity of brain cells and the strength of their connections. Specifically, they made recordings from brain slices of the mice to examine the function of synapses, which are the points of communication between nerve cells. They focused on inhibitory synapses, the connections made by inhibitory nerve cells. They measured how these synapses responded to repeated stimulation and assessed a property called short-term depression, which indicates the maturity of the synapse. Mature synapses typically show less short-term depression. They also investigated a form of plasticity at inhibitory synapses called inhibitory long-term depression, to see if cannabinoid receptors on either cell type were necessary for this particular type of synaptic change.
In addition to these detailed cellular studies, the researchers also used optical imaging, a technique that allows them to visualize brain activity across larger areas. This allowed them to measure the overall response of the visual cortex to stimulation of each eye, providing a measure of ocular dominance plasticity in the intact brain. Furthermore, to get a more detailed picture across different layers of the brain, they used electrophysiological recordings in living mice, employing probes that could record activity at different depths in the visual cortex. This allowed them to see if the effects of removing cannabinoid receptors differed in different layers of the brain’s visual processing center. Throughout their experiments, they carefully compared the genetically modified mice to normal mice to determine the specific role of cannabinoid receptors in different brain cell types for brain development and plasticity.
The researchers found that removing cannabinoid receptors from astrocytes had a significant impact on brain development and plasticity, while removing them from nerve cells did not. “The finding that genetically removing cannabinoid receptors from neurons had no effect on brain plasticity was surprising (but in line with our hypothesis),” Min told PsyPost.
They found that in mice lacking cannabinoid receptors on astrocytes, the inhibitory synapses in the visual cortex did not mature normally. These synapses remained in a more immature state, showing more short-term depression than those in normal mice. This indicated that astrocytes, through their cannabinoid receptors, play a role in the normal maturation of inhibitory connections in the brain.
Perhaps most surprisingly, the researchers found that ocular dominance plasticity was severely impaired in mice without cannabinoid receptors on astrocytes. When one eye was temporarily covered, the brains of these mice were much less able to adapt to this change compared to normal mice. The visual cortex of these mice did not show the typical shift in activity towards the uncovered eye, demonstrating a significant deficit in brain plasticity.
Interestingly, mice without cannabinoid receptors on nerve cells showed normal ocular dominance plasticity, adapting to the change in visual input just like the control mice. This strongly suggested that astrocytes, and not nerve cells, are the key cell type through which cannabinoid receptors influence this form of brain plasticity during development. This effect on plasticity was observed across all layers of the visual cortex, but was particularly pronounced in the deeper layers of this brain region.
When the researchers examined inhibitory long-term depression, a different form of plasticity at inhibitory synapses, they found that it was not affected by removing cannabinoid receptors from either astrocytes or nerve cells. This suggests that while astrocyte cannabinoid receptors are crucial for the maturation of inhibitory synapses and overall brain plasticity related to visual input, they are not necessary for all forms of plasticity at these synapses.
The findings indicate “that cannabinoid receptors on astrocytes play a key role in brain plasticity during development,” Min explained. “Early adjustments of the visual system are disrupted when the cannabinoid receptor is genetically removed from astrocytes.”
The researchers acknowledged some limitations to their study. One limitation is that in the genetically modified mice, cannabinoid receptors were not completely removed from all astrocytes. It is possible that some receptors remained, and this might have lessened the observed effects. Another point is that the removal of cannabinoid receptors from astrocytes was not limited to the visual cortex; it occurred throughout the brain. It is possible that the observed effects on visual plasticity could be indirectly influenced by changes in other brain regions, although the focus on the visual cortex and specific visual plasticity measures makes a direct effect within the visual system more likely.
For future research, the scientists suggest exploring the precise mechanisms by which cannabinoid receptors on astrocytes influence inhibitory synapse maturation and brain plasticity. It would also be valuable to investigate if more complete removal of cannabinoid receptors from astrocytes leads to even stronger effects. Understanding the specific role of astrocyte cannabinoid receptors could provide important insights into the potential risks of cannabis use, particularly during adolescence when the brain is still developing and highly plastic, and could inform strategies to mitigate any potential negative consequences.
“The young brain is very plastic and easily adjusts to alterations in sensory inputs,” Min said. “If we understand which mechanisms contribute to this increased plasticity, we might be able to re-instate levels of young plasticity in the adult brain. This study contributes to a better understanding of which plasticity mechanisms make the young brain plastic.”
The study, “Inhibitory maturation and ocular dominance plasticity in mouse visual cortex require astrocyte CB1 receptors,” was authored by Rogier Min, Yi Qin, Sven Kerst, M. Hadi Saiepour, Mariska van Lier, and Christiaan N. Levelt
