Summary: New research reveals that chronic brain inflammation can directly lead to repetitive behaviors, often seen in conditions like autism spectrum disorder (ASD) and obsessive-compulsive disorder (OCD). In mice with a mutated NLRP3 gene, inflammation activated microglia to release IL-1β, overstimulating NMDA glutamate receptors responsible for excitatory brain signals.
This overactivation triggered anxiety and meaningless repetitive actions. Administering memantine or interleukin-1RA, both FDA-approved drugs, normalized brain activity and stopped the behaviors.
Key Facts:
- Inflammation Link: Chronic brain inflammation from NLRP3 mutation causes repetitive behaviors via NMDA receptor overactivation.
- Drug Repurposing: FDA-approved drugs memantine and interleukin-1RA reversed these effects in mice.
- Cytokine Cascade: IL-1β released by microglia plays a key role in triggering behavioral symptoms.
Source: DGIST
Repetitive behaviors, such as repeatedly checking whether doors are locked or washing one’s hands multiple times, may be experienced by anyone at least once and may result in ASD or OCD if the behaviors are severe.
Although neural circuit abnormalities and genetic factors have been regarded among the potential causes of repetitive behaviors, no direct association between brain inflammation and these behaviors was identified until Professor Um’s research team suggested that brain inflammation may play a critical role in repetitive behaviors.
The research involved mice with a mutated NLRP3 gene. This gene mutation stimulates a chronic inflammatory response by immune cells in the brain that are called microglia.
Prolonged inflammation over-activates N-methyl-D-aspartate (NMDA) glutamate receptors, which are important for excitatory neurotransmission. The consequences are meaningless repetitive behaviors and anxiety symptoms.
Having noted that over-activate NMDA glutamate receptors cause repetitive behaviors, the research team administered a drug called memantine, a commercially available treatment for Alzheimer’s disease, to the mice with the NLRP3 gene mutation and found that the drug significantly reduced meaningless repetitive behaviors and that NMDA glutamate activity returned to normalcy.
These results indicate that over-active NMDA glutamate receptors directly cause repetitive behaviors.
The researchers also found clues about how brain inflammation stimulates NMDA glutamate receptors. They have revealed that inflamed microglia release a pro-inflammatory substance (cytokine) called interleukin-1 beta (IL-1β), which affects NMDA glutamate receptors.
When the mice were injected with a drug that blocks the activity of interleukin-1 receptors (interleukin-1RA), it suppressed overactivity in the NMDA glutamate receptors, and the repetitive behaviors disappeared.
Memantine and interleukin-1RA (product name: Anakinra), which were used in the study, are treatments that are approved by the United States Food and Drug Administration (FDA) and are currently used to manage Alzheimer’s disease and rheumatoid arthritis.
These readily available drugs of proven safety and efficacy can be repurposed to treat ASD and OCD, negating the need to develop new drugs. As a strategy, drug repurposing reduces drug discovery time and costs, helping to commercialize treatments.
Professor Jiwon Um said, “This study has demonstrated that chronic brain inflammation induces overactivity in NMDA glutamate receptors, resulting in repetitive behavioral disorders.
“We may be able to suggest a new therapeutic approach for treating ASD and OCD, which are often accompanied by repetitive behaviors.”
Dr. Hyeji Jung of the Department of Brain Sciences within the DGIST was the first author.
The research findings were published online on May 7, 2025, in Cell Reports, a scientific journal.
Funding: The study was funded by the Ministry of Science and Information Communication Technology and the National Research Foundation of Korea as part of the Basic Research Center Support Project and the Mid-Career Researcher Support Project.
About this inflammation, ASD, and OCD research news
Author: Wankyu Lim
Source: DGIST
Contact: Wankyu Lim – DGIST
Image: The image is credited to Neuroscience News
Original Research: Open access.
“The NLRP3 inflammasome in microglia regulates repetitive behavior by modulating NMDA glutamate receptor functions” by Jiwon Um et al. Cell Reports
Abstract
The NLRP3 inflammasome in microglia regulates repetitive behavior by modulating NMDA glutamate receptor functions
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.
