Researchers have identified a direct link between the degradation of myelin, the protective sheath covering nerve fibers, and the onset of seizures in multiple sclerosis. A preclinical study using a mouse model demonstrated that as myelin deteriorates in the hippocampus, a brain region critical for memory, the brain’s electrical stability is compromised, making seizures significantly more likely. The findings provide a concrete biological explanation for a debilitating complication that affects a notable subset of MS patients.
Published in the journal Neurobiology of Disease, the research addresses a crucial gap in understanding why 4–5% of individuals with multiple sclerosis experience seizures, which are associated with worse cognitive outcomes and faster disease progression. By uncovering the specific neurochemical changes that occur during demyelination, the study paves the way for developing targeted therapies that could prevent seizures without the broad side effects of current medications, such as fatigue and cognitive dulling. The work was led by Seema Tiwari-Woodruff, a professor of biomedical sciences at the University of California, Riverside, School of Medicine.
An Imbalance in Brain Signaling
The investigation pinpointed a critical shift in the brain’s chemical balance as a primary driver of seizure activity. As myelin eroded in the mouse models, researchers observed a corresponding rise in glutamate, the brain’s main excitatory neurotransmitter. Simultaneously, levels of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter, decreased. This disruption creates a state of hyperexcitability, where neurons are more prone to firing uncontrollably, leading to seizures. The study suggests that the damage to specific GABA-producing neurons in the hippocampus, caused by the loss of their protective myelin, is a key reason for this imbalance and the resulting susceptibility to seizures.
The Hippocampus as a Key Region
The study focused heavily on the hippocampus, a part of the brain long known for its essential role in learning and memory and its vulnerability to seizure activity. The researchers tracked the progression of myelin loss in this area and found a direct correlation with the frequency and severity of seizures in the animal models. Multiple sclerosis is characterized by the immune system attacking myelin throughout the central nervous system, but this research highlights the demyelination in the hippocampus as a specific trigger for seizures, explaining why not all MS patients develop this particular symptom.
Modeling Demyelination in the Lab
A Progressive Approach
To simulate the slow and progressive nature of myelin loss seen in human MS patients, the scientific team utilized a well-established method known as the cuprizone diet mouse model. This toxic diet induces demyelination over a period of weeks. The researchers conducted behavioral assessments and brain recordings throughout the process. Their results were stark: after 12 weeks of progressive demyelination, nearly 80% of the mice displayed clear signs of seizure activity. This was a substantial increase from the 40% observed earlier in the disease process, confirming that worsening myelin damage directly increased seizure likelihood.
A More Accurate Research Tool
This experimental model offers a significant advantage over traditional epilepsy research, which often relies on inducing acute physical or chemical damage to brain tissue to trigger seizures. Tiwari-Woodruff noted that their approach does not destroy brain tissue but instead models the gradual myelin degradation that occurs in the actual disease. This makes it a more faithful and powerful tool for studying the specific mechanisms of MS-related seizures and for testing potential new treatments.
Investigating the Role of Support Cells
The research team is now expanding its investigation to understand the function of astrocytes, a type of glial cell that provides support and protection for neurons in the brain. One of the key roles of astrocytes is to remove excess glutamate from the space around neurons, preventing overstimulation. The scientists hypothesize that if these support cells are damaged or impaired as part of the MS disease process, they may be unable to clear glutamate effectively. This failure would lead to a buildup of the excitatory neurotransmitter, allowing brain signals to go unchecked and ultimately causing seizures. This line of inquiry could reveal another critical target for therapeutic intervention.
New Pathways for Future Treatment
The insights gained from this study open the door for developing novel treatments that are far more precise than existing anti-seizure medications. Current drugs often work by broadly suppressing brain activity, which can lead to unwanted side effects that diminish a patient’s quality of life. The new research suggests that therapies could be designed to specifically address the glutamate-GABA imbalance or to protect the particular cells involved in the hippocampus. Tiwari-Woodruff emphasized that the goal is “targeted modulation, not blanket suppression,” as glutamate is essential for normal brain function. Blocking it completely would be detrimental, making a targeted approach essential.
Clinical Significance for MS Patients
While symptoms like vision problems, fatigue, and coordination issues are more commonly associated with multiple sclerosis, seizures represent a serious and often misunderstood complication. Studies have shown that MS patients are three to six times more likely to develop epilepsy than the general population. This research provides a clear biological explanation for this increased risk, offering clarity to patients who experience seizures. By understanding the underlying cause, the medical community can move closer to developing effective strategies to manage and prevent seizures in people living with MS, ultimately improving their cognitive outcomes and quality of life.