Tuberous sclerosis complex (TSC) is a multi-system genetic disorder associated with a variety of physical manifestations caused by mutations in TSC1 or TSC2, which encode proteins that negatively regulate mTOR (mammalian/mechanistic target of rapamycin) complex 1 (mTORC1). TSC is also neurodevelopmental disorder with the behavioral and psychiatric problems. These neuropsychiatric multidimensional manifestations are termed "TAND" (TSC-associated neuropsychiatric disorders). TAND is burden for patients, however the cause of neuropsychiatric and behavioral abnormalities remains uninvestigated. In our previous investigations of the mechanisms of melanogenesis, we constructed Tsc2 conditional knockout mice in which Cre recombinase was placed under the control of regulatory elements from the Mitf-M gene (Tsc2 cKO). These mice developed spontaneous neural epileptic activity as well. Here, we further analyzed behaviors of these Tsc2 cKO mice in more detail and confirmed that these mice exhibits a neuropsychiatric phenotype such as attention deficit hyperactivity disorder (ADHD), the increased anxiety-like behavior and probable autism spectrum disorder (ASD) as well as epileptic seizures. Furthermore, we found that the intraperitoneal mTOR inhibitor Sirolimus (also called rapamycin) reduced neuropsychiatric symptoms in these cKO mice and significantly changed the microglial morphology of the glomerulus of the olfactory to that with extended protrusions in cKO mice, on the other hand the morphology of microglia without sirolimus was almost the same between cKO and control mice. It is suggested that the microglial decreased phagocytosis in Tsc2 cKO mice may be involving in TAND.

ESDR174 - The microglial decreased phagocytosis in olfactory bulb is responsible for neuropsychiatric disorders in tuberous sclerosis complex model mice.

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING