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The role of neuroinflammation in ASD-related behaviors, hyper-excitability and epilepsy

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United States

The biological basis of autism spectrum disorder (ASD) is poorly understood, but research strongly suggests that, aside from genetic predisposition, the body's immune system may play a major role. The immune system produces the familiar momentary inflammation in response to injury or infection. However, it was recently realized that the brain also has an immune system, which in ASD, produces long-term brain inflammation. This discovery is pivotal because the research team has recently shown that inflammation can cause the brain to over-respond to stimulation and also to have epileptic seizures. It is not surprising that 30% of ASD patients develop epilepsy, 50% display epilepsy-like signals in their brain waves even without seizures, and about 32% of patients with epilepsy also have ASD. What is surprising is that the connection between brain inflammation, an over-responsive brain, and how this might produce seizures and interfere with normal behavior, has been virtually ignored in scientifically controlled animal studies of ASD. This study represents a unique collaboration to study how brain inflammation can cause epilepsy, and have discovered ways to suppress this with drugs that regulate the brain's immune inflammation. The study will apply the investigators' experience to understanding, and possibly treating, ASD. They will adapt two animal models of ASD that involve maternal infections (a common cause of ASD in human offspring), that produce ASD-like behavior, and study the brain's electrical activity. These models produce brain inflammation, and should show electrical signs of over-responsiveness to sensory stimulation and epilepsy. The investigators will then test a drug (MN166) in ASD, which they have used to reduce epilepsy, anxiety, and damage following traumatic brain injury in rats. Given the strong association between human ASD and epilepsy, human ASD and immune brain inflammation, and close ties between immune brain inflammation and epilepsy, this project has the potential to establish a new and successful paradigm for studying and understanding ASD. However, MN166, was also chosen because it is safe for human use, can be taken orally, and has been approved by the Food and Drug Administration (FDA) for clinical trials in treating human chronic pain produced by immune inflammation. Therefore, if the study is successful, the results may yield an accelerated path for eventual use in ASD patients.