The Surprising Role of Cannabis in Reshaping the Brain

Recent research has revealed an unexpected role for CB1 receptors in cells called astrocytes. Astrocytes are glial cells that were long thought to serve as support cells for neurons, but we now know that they play active roles in regulating synaptic plasticity. This study provides important insights into how non-neuronal cells, such as astrocytes, play a critical role in brain circuit development and learning.

The human brain is shaped by experience, especially during early life. This occurs through neuronal circuits that adapt to changes in the environment. However, this ability to adapt, or plasticity, is much more intense in the young brain than in the adult.

These critical postnatal periods are phases in which the brain displays an exceptional ability to reorganize itself and learn, which are essential for cognitive and sensory development.

One of the key molecules that regulate this plasticity in the brain is endocannabinoids. They act through receptors called CB1 (CB1Rs), which play a crucial role in the maturation of inhibitory circuits in the cerebral cortex.

In particular, in the developing primary visual cortex (known as V1), these receptors regulate the formation and maturation of inhibitory synapses, which are connections between neurons that control brain activity and maintain the balance of neural networks.

In V1, inhibitory synapses undergo a maturation process. Initially, they exhibit a characteristic called short-term depression, where the transmission of neuronal signals is rapidly weakened after repeated stimulation.

As they mature, this short-term depression diminishes, allowing for more stable and efficient synapses. During this immature phase, synapses can also undergo a phenomenon called endocannabinoid-induced long-term depression (iLTD), which disappears as synapses mature.

Organization of the primary visual cortex. Source: Lyes Bachatene, Vishal Bharmauria and Stéphane Molotchnikoff. DOI: 10.5772/46011

The completion of this maturation coincides with the beginning of the critical period of plasticity, a phase in which the brain is most receptive to change and learning.

Studies in mice and rats have shown that inhibitory maturation in V1 occurs around 28 to 35 days of age (in mice) and approximately one week later in rats.

Raising animals in the dark, which prevents visual stimulation, prolongs this critical period, suggesting that environmental stimulation is necessary for synaptic maturation to complete in a timely manner.

Recent research has revealed an unexpected role for CB1 receptors in cells called astrocytes. Astrocytes are glial cells that have long been thought of as supporting cells for neurons, but we now know that they play active roles in regulating synaptic plasticity.

By removing CB1 receptors specifically from astrocytes in V1, the scientists observed that the maturation of inhibitory synapses was impaired and critical period plasticity was significantly reduced. In contrast, removing these receptors from interneurons, another cell type involved in brain signaling, did not have the same impact.

The researchers found that removing CB1 receptors from astrocytes meant that the brain could less easily adjust to changes during development. A) Deactivating CB1 receptors on interneurons has no effect on flexibility. B) Deactivating CB1 receptors on astrocytes makes the brain less flexible and plasticity decreases. Source: Rogier Min and Christiaan Levelt’s, the Netherlands Institute for Neuroscience.

These findings highlight the importance of astrocytes and their CB1 receptors in critical period plasticity in V1. The absence of these receptors in astrocytes compromises the maturation of inhibitory synapses, directly affecting the onset of the critical period of ocular plasticity, a phase in which the brain adjusts its response to visual stimuli.

This study provides important insights into how non-neuronal cells, such as astrocytes, play an essential role in brain circuit development and learning.

Ultimately, the results suggest that interventions in the endocannabinoid system may have therapeutic implications for developmental disorders related to brain plasticity, although more research is needed to fully understand these mechanisms.

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Inhibitory maturation and ocular dominance plasticity in mouse visual cortex require astrocyte CB1 receptors

Rogier Min, Yi Qin, Sven Kerst, M. Hadi Saiepour, Mariska van Lier, and Christiaan N. Levelt

iScience. Volume 27, Issue 12111410, December 20, 2024

DOI: 10.1016/j.isci.2024.111410

Abstract:

Endocannabinoids, signaling through the cannabinoid CB1 receptor (CB1R), regulate several forms of neuronal plasticity. CB1Rs in the developing primary visual cortex (V1) play a key role in the maturation of inhibitory circuits. Although CB1Rs were originally thought to reside mainly on presynaptic axon terminals, several studies have highlighted an unexpected role for astrocytic CB1Rs in endocannabinoid mediated plasticity. Here, we investigate the impact of cell-type-specific removal of CB1Rs from interneurons or astrocytes on development of inhibitory synapses and network plasticity in mouse V1. We show that removing CB1Rs from astrocytes interferes with maturation of inhibitory synaptic transmission. In addition, it strongly reduces ocular dominance (OD) plasticity during the critical period. In contrast, removing interneuron CB1Rs leaves these processes intact. Our results reveal an unexpected role of astrocytic CB1Rs in critical period plasticity in V1 and highlight the involvement of glial cells in plasticity and synaptic maturation of sensory circuits.