How Endocannabinoids Keep the Brain in Balance

Summary: Endocannabinoids actively balance neural connections, allowing cells to either activate or inhibit each other. The findings shed light on the role endocannabinoids play in learning and some psychiatric disorders.

Source: Utrecht University

Although wisdom comes with age, our brain does not store every single experience or lesson learned. In addition to learning and remembering, our brains are also equipped to forget irrelevant things or drop unused skills.

In order to find a balance in this, brain cells constantly communicate with each other through connections that activate or inhibit the cells. Researchers from Utrecht University discovered that brain cells can form new, inhibitory connections via so-called endocannabinoid.

They announce their discovery in Journal of Neuroscience.


Endocannabinoids derive their name from the cannabis plant, which contains similar substances. The researchers discovered the role of endocannabinoids when they induced brain cells of mice to strengthen activating connections. In response, the brain cells also started making new inhibitory connections. The researchers found that endocannabinoids kickstarted the new connections.

Surprisingly active role

The researchers were surprised to find that these substances play such an active role. “Nobody expected this from endocannabinoids,” says research leader Corette Wierenga, neurobiologist at Utrecht University.

It was already known that endocannabinoids can influence the functioning of our brains. But until now researchers assumed that the substances were merely involved in adjusting existing connections. “Now it appears that the system of endocannabinoids can actively push the production of new inhibitory connections, with which brain cells actively regulate the balance.”

Psychiatric disorders caused by imbalance

The discovery could help scientists to better understand how psychiatric disorders and other abnormalities in the brain develop. In many of these disorders, the balance between inhibitory and activating connections is disturbed. During an epileptic seizure, for example, this balance is seriously disturbed. Although in many other disorders the disturbance is more subtle, for example in schizophrenia, the impact can still be equally profound.

Unbalance caused by cannabis

The balance between activating and inhibiting connections in our brain is constantly being adjusted in response to our experiences. Whenever we experience something, the connections change, and the brain must restore the balance. Cannabis use can disrupt that balance.

“Occasional cannabis use will not seriously disturb the balance,” says Wierenga. “But if the balance is disturbed for a longer period, it can cause problems. For example, children of mothers who smoked marijuana during pregnancy can experience problems with neurological development.”

Early stages of life

The balance is especially important in early stages of life, Wierenga says. “During our development, brain connections are constantly changing. Especially during that period, it is important that inhibitory and activating connections remain coordinated. If the coordination is malfunctioning or disturbed, you can imagine that the system becomes disrupted. And unfortunately, disruptions that occur so early cannot be easily repaired later in life.”

This shows a brain
Researchers at Utrecht University found that the substances actively balance connections in the brain that allow cells to either activate or inhibit each other. Image is in the public domain

According to Wierenga, such disruptions can lead not only to loss of memory, but also initiate more serious consequences. For example, the brain might grow out to less adaptive to stressful situations. “When this happens, things get out of hand more easily in the brain, because inhibition and activation are out of balance. That could lead to learning and behavioural problems.”

Predicting and preventing disorders

Creating a deeper understanding of the role endocannabinoids play in the brain, could lead to psychiatric disorders being more predictable or even prevented in the future. The publication in Journal of Neuroscience now sets out a new direction in which more knowledge can be built up. Wierenga: “Ultimately, as a researcher, we want to understand how brain cells coordinate the balance and what happens when that balance is disturbed.

About this neuroscience research news

Author: Press Office
Source: Utrecht University
Contact: Press Office – Utrecht University
Image: The image is in the public domain

Original Research: Closed access.
Axonal CB1 receptors mediate inhibitory bouton formation via cAMP increase and PKA” by Jian Liang, Dennis L. H. Kruijssen, Aniek C. J. Verschuuren, Bas J. B. Voesenek, Feline F. W. Benavides, Maria Sáez Gonzalez, Marvin Ruiter, Corette J. Wierenga. Journal of Neuroscience


Axonal CB1 receptors mediate inhibitory bouton formation via cAMP increase and PKA

Experience-dependent formation and removal of synapses are essential throughout life. For instance, GABAergic synapses are removed to facilitate learning, and strong excitatory activity is accompanied by formation of inhibitory synapses to maintain coordination between excitation and inhibition.

We recently discovered that active dendrites trigger the growth of inhibitory synapses via CB1 receptor-mediated endocannabinoid signaling, but the underlying mechanism remained unclear.

Using two-photon microscopy to monitor the formation of individual inhibitory boutons in hippocampal organotypic slices from mice (both sexes), we found that CB1 receptor activation mediated the formation of inhibitory boutons and promoted their subsequent stabilization.

Inhibitory bouton formation did not require neuronal activity and was independent of Gi/o protein signaling, but was directly induced by elevating cAMP levels using forskolin and by activating Gs proteins using DREADDs. Blocking PKA activity prevented CB1 receptor-mediated inhibitory bouton formation. Our findings reveal that axonal CB1 receptors signal via unconventional downstream pathways and that inhibitory bouton formation is triggered by an increase in axonal cAMP levels.

Our results demonstrate an unexpected role for axonal CB1 receptors in axon-specific, and context-dependent, inhibitory synapse formation.

Significance statement

Coordination between excitation and inhibition is required for proper brain function throughout life. It was previously shown that new inhibitory synapses can be formed in response to strong excitation to maintain this coordination, and this was mediated by endocannabinoid signaling via CB1 receptors.

As activation of CB1 receptors generally results in suppression of synaptic transmission, it remained unclear how CB1 receptors can mediate the formation of inhibitory synapses.

Here we show that CB1 receptors on inhibitory axons signal via unconventional intracellular pathways and that inhibitory bouton formation is triggered by an increase in axonal cAMP levels and requires PKA activity.

Our findings point to a central role for axonal cAMP signaling in activity-dependent inhibitory synapse formation.

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