When the Brain Is On Fire: The Silent Root of Repetitive Behaviors in Autism and OCD

Researchers have discovered that inflammation in the brain can cause symptoms such as anxiety and repetitive behaviors. In tests on mice, an immune system protein called NLRP3 inflammasome, when overactivated, altered the way neurons communicate and caused these symptoms. The study showed that blocking this inflammation or the exaggerated communication of neurons helped to normalize the animals' behavior. These findings help to better understand how inflammation may be behind some mental disorders and point the way to new treatments.

You've heard that inflammation in the body can cause pain or fever, right? But what many still don't know is that the brain can also suffer from inflammation, and this may be linked to problems such as anxiety, depression and other mental disorders. This type of inflammation is called neuroinflammation, and has aroused a lot of interest among scientists in recent years.

Our body has a defense system that recognizes when something is wrong, such as an infection or an injury. One of the tools of this system are inflammasomes, structures that function as internal sensors.

When they perceive an “alert” in the body, they trigger an inflammatory response to protect the body.

The problem is that if this inflammation is active for too long or occurs for no real reason, it can start to impair brain function. Recent research shows that people with anxiety, depression, and post-traumatic stress often have high levels of inflammatory substances in their bodies and brains.

Among these sensors, one of the most studied is the NLRP3 inflammasome. It goes into action when the body detects signs of danger, even if these signals come from damaged cells and not from a real threat.

When NLRP3 is activated, it stimulates the production of a molecule called IL-1β, which can directly affect the functioning of neurons, the cells that transmit information in the brain.

This inflammation process is important for defending the body, but when it goes unchecked, it can contribute to diseases such as Alzheimer's, Parkinson's and mood disorders. IL-1β, for example, can alter memory, increase anxiety and cause symptoms similar to depression.

In addition, NLRP3 activates brain cells called microglia and astrocytes, which are like the “soldiers” of the brain's immune system. When they are overactivated, these cells can further increase inflammation and worsen brain function.

To better understand how all this works, scientists created mice with a genetic mutation in the NLRP3 inflammasome. This mutation causes it to be on all the time, as if the body were always on alert, even in the absence of any real threat. This constant activation generates continuous inflammation.

In this experiment, the scientists placed the mutation only in the microglia, to see the effects on the brain more precisely. They analyzed the behavior of the mice, the activity of the neurons and used high-definition imaging.

What they found was striking: the mice displayed repetitive behaviors and signs of anxiety, similar to what we see in human mental disorders.

When the researchers examined the brains of these animals, they noticed that the connections between neurons were more active than normal, especially those that use the NMDAR receptor, involved in functions such as memory and learning.

This overactivity can be dangerous. Worse, the inflammatory molecule IL-1β appeared to be further increasing this overactivation by stimulating a specific part of the receptor called GluN2A, which was most commonly found on the surface of neurons.

To test whether this was actually causing the altered behaviors, the researchers gave them drugs that blocked either the NMDAR receptor or the IL-1β receptor. The result? The anxiety symptoms and repetitive behaviors disappeared.

These results are very important. They show that, even without other brain diseases, inflammation alone can cause changes in behavior and emotional state. What’s more, they point to possible targets for the development of new treatments for mental disorders linked to inflammation, such as IL-1β, the NMDAR receptor and the NLRP3 inflammasome itself.

READ MORE:

The NLRP3 inflammasome in microglia regulates repetitive behavior by modulating NMDA glutamate receptor functions

Hyeji Jung, Byeongchan Kim, Gyubin Jang, Hyeonho Kim, Ae-Ree Lee, Sung-Hyun Yoon, Kyung-Seo Lee, Gaeun Hyun, Younghye Kim, Jaewon Ko, Je-Wook Yu, and Ji Won Um

CellPress. Volume 44, Issue 5115656 May 27, 2025

DOI: 10.1016/j.celrep.2025.115656 

Abstract:

Neuroinflammation is a well-established risk factor for various neurological disorders and cognitive decline. However, the precise molecular mechanisms linking inflammation with neuropsychiatric symptoms remain unclear. Here, using NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3) conditional knockin (cKI) mice harboring a D301N point mutation originating in patients with autoinflammatory diseases, we found that activation of the NLRP3 inflammasome by administration of lipopolysaccharide induced anxiety-like and repetitive behaviors frequently found in patients with neuropsychiatric disorders, as well as increasing NMDAR (N-methyl-D-aspartate receptor)-mediated excitatory synaptic functions in the medial prefrontal cortex of mice. In addition, interleukin 1β (IL-1β), a downstream cytokine of the NLRP3 inflammasome, enhanced NMDAR activation and increased surface levels of the selective NMDAR subunit GluN2A in cultured cortical neurons. Strikingly, treatment with an NMDAR antagonist or IL-1 receptor antagonist completely normalized the specific behavioral deficits in Nlrp3D301N-cKI mice. Collectively, our results demonstrate that NLRP3-mediated neuroinflammation elicits repetitive behavior through impaired NMDAR functions.