INTRODUCTION: Tuberous Sclerosis Complex (TSC) is a rare genetic disorder caused by mutations in TSC1 or TSC2, genes that encode for hamartin and tuberin respectively, normally suppress mTORC1 signaling. Loss of this inhibition leads to mTOR pathway hyperactivation, resulting in abnormal cell growth and a broad spectrum of clinical manifestations, including benign tumors, epilepsy, and TSC-associated neuropsychiatric disorders (TANDs). Neuropsychiatric disorders such as autism spectrum disorder (ASD), anxiety, and intellectual disability show substantial inter-individual variability, even among patients with similar mutations, suggesting that environmental factors contribute alongside genetic predisposition to neurodevelopmental outcomes. Inflammation during early development is a potential modifier of TSC phenotypes. Epidemiological studies have linked maternal infection and prenatal immune activation with an increased risk of ASD in offspring, indicating that immune signals may interact with underlying genetic vulnerabilities to alter brain development. Among inflammatory mediators, interleukin-6 (IL-6) is a pleiotropic cytokine produced by multiple immune cell types in response to infection or tissue damage. IL-6 can cross the blood–brain barrier and has been implicated in neuroinflammatory and neuropsychiatric conditions, including ASD and intellectual disability.

AIM(S): To investigate gene-environment interactions by microinjecting IL-6 into the bloodstream of TSC background zebrafish larvae.

METHOD(S): Breeding and Genotyping of TSC2 fish, Microinjections (2dpf, 3dpf), Behavioral test (Open field test), WMAS, imaging, and analysis.

RESULTS: My preliminary data shows that IL-6 microinjections into the duct of Cuvier increase anxiety-like behaviors and induce repetitive stereotypical swimming patterns that may reflect ASD in TSC background.

CONCLUSIONS: Early inflammatory signaling, with a focus on IL-6 microinjections into the duct of Cuvier, influences neural development and behavior in a TSC background.

FINANCIAL SUPPORT: Sonata bis:2023/50/E/NZ3/00252