IL-6 Molecule May Be Behind Abnormal Nerve Cell Communication in Fragile X, Study Suggests

High levels of a pro-inflammatory molecule called interleukin (IL)-6 in the brain could be key to abnormal neuronal communication in fragile X syndrome, a mouse study reports.

The study, “Regulation of IL-6 Secretion by Astrocytes via TLR4 in the Fragile X Mouse Model,” appeared in the journal Frontiers in Molecular Neuroscience.

Fragile X, the most common genetic cause of autism, is characterized by a mutation in the FMR1 gene, which disrupts the production of the FMRP protein. Under normal conditions, FMRP is produced in neurons, astrocytes — a cell type with various functions, including the formation of the blood-brain barrier and response to injury — and oligodendrocytes — the cells responsible for the production of the protective layer of nerve fibers, called myelin.

This protein is also implicated in formation and structure of the synapse, the point of contact between two nerve cells that allows them to communicate.

Recent evidence has shown that astrocytes play a key role in regulating the synapse through the release of specific molecules. Activation of TLR4, an immune system protein found at the surface of astrocytes, increases the release of IL-6 — a type of molecule called a cytokine involved in immune responses.

Although the primary functions of IL-6 have been linked to immune responses involved in brain development, a recent study suggested that IL-6 is increased in the cerebellum of autistic patients, which, in turn, alters synapse formation.

Researchers from McMaster University in Canada compared the production of TLR4, IL-6, and tenascin C (TNC) — a protein secreted by astrocytes that activates TLR4 and is involved in synapse development and inflammation — in the brain cortex of mice lacking the FMR1 gene — a model for human fragile X — during the first three weeks after birth, when synapse formation and maturation are key.

To better understand the function of TLR4, researchers also administered TNC and the inflammatory activator LPS (which binds to TLR4) to astrocytes grown in the laboratory. They then used a TLR blocker, LPS-RS, to assess its impact on inflammatory cytokine production.

Results showed that the release of TNC and IL-6 was significantly increased in astrocytes lacking FMR1, compared with controls. While both TNC and LPS induced the secretion of IL-6 by cells (specifically in control astrocytes), the TLR4 blocker LPS-RS had the opposite effect in fragile X mouse astrocytes only, leading scientists to hypothesize that these altered astrocytes may be more sensitive due to their higher TNC and IL-6 levels.

Production of TNC and IL-6, but not TLR4, in the fragile X mouse cortex was also significantly elevated after birth.

“These findings suggest that elevated IL-6, which has been previously noted in the autistic brain, could be the contributing factor in abnormal synapse formation,” the investigators wrote. “By assessing the cellular mechanisms involved, a novel therapeutic option could be made available to target abnormalities of synaptic function seen in [fragile X].”