Reduced epilepsy development in synapsin 2 knockout mice with autistic behavior following early systemic treatment with interleukin-6 receptor antibody.

Scientists studied mice with autism-like behaviors that also develop seizures. They gave some mice a treatment that blocks a protein called IL-6 before seizures started, and others after seizures began. The early treatment reduced seizure development, but the later treatment didn't help. However, the treatment didn't improve the autism-like behaviors, memory, mood, or sleep problems.

This suggests that this particular treatment might help prevent seizures in some cases but doesn't address other autism-related challenges.

This preclinical study investigated whether blocking IL-6 receptor signaling could reduce epilepsy development in Syn2 knockout mice, which exhibit autism-like behaviors and develop seizures. Researchers treated mice with IL-6 receptor antibody either before seizure onset (1 month) or after seizure debut (3 months). Early treatment significantly reduced seizure development and frequency, but late treatment showed no benefit. Importantly, the treatment did not improve autism-related behaviors, cognitive function, mood, or sleep patterns.

The neuroinflammatory response and synaptic protein imbalances in the brain remained unchanged despite seizure reduction, suggesting IL-6 receptor signaling specifically influences epilepsy development rather than broader autism-related brain changes.

While promising for seizure prevention in autism, IL-6 receptor antibody treatment appears ineffective for core autism symptoms. Early intervention timing may be critical. Further research needed to determine human applicability and safety before clinical translation.

Study conducted only in mouse models, which may not translate to human autism and epilepsy. Sample sizes not reported. Limited to one specific genetic model (Syn2 KO mice). Cannot determine optimal dosing or treatment duration for potential human applications.

Individuals with autism spectrum disorder (ASD) have an increased risk of developing epilepsy. Both ASD and epilepsy have been associated with increased levels of immune factors in the blood, including the proinflammatory cytokine interleukin 6 (IL-6). Mice lacking the synapsin 2 gene (Syn2 KO) exhibit ASD-like behavior and develop epileptic seizures. Their brains display neuroinflammatory changes including elevated IL-6 levels.

We aimed to investigate the effect of systemic IL-6 receptor antibody (IL-6R ab) treatment on seizure development and frequency in Syn2 KO mice. Weekly systemic (i.p.) injections of IL-6R ab or saline were given to Syn2 KO mice starting either early in life at 1 month of age, before seizure debut or at 3 months of age, directly after seizure debut and continued for 4 or 2 months, respectively. Seizures were provoked by handling the mice three times per week. The neuroinflammatory response and synaptic protein levels in the brain were determined by ELISA, immunohistochemistry and western blots.

In an additional group of Syn2 KO mice, with IL-6R ab treatment early in life, ASD-related behavioral tests including social interaction and repetitive self-grooming, as well as cognitive memory and depressive-/anxiety-like tests, and actigraphy measurements of circadian sleep-awake rhythm were analyzed. The IL-6R ab treatment reduced seizure development and frequency in Syn2 KO mice when initiated before, but not after, seizure debut. However, early treatment did not reverse the neuroinflammatory response or the imbalance in synaptic protein levels in the brain previously reported in Syn2 KO mice. The treatment did not affect social interaction, performance in memory, depressive-/anxiety-like tests or the sleep-awake rhythm of Syn2 KO mice.

These findings suggest the involvement of IL-6 receptor signaling during epilepsy development in Syn2 KO mice, without significant alterations of the immune reaction in the brain, and independently of cognitive performance, mood and circadian sleep-awake rhythm.