mTORC1 hyperactivation causes sensory integration deficits due to habenula impairment

Abstract

AbstractMechanistic target of rapamycin complex 1 (mTORC1) is an integration hub for extracellular and intracellular signals necessary for proper brain development. Hyperactivation of mTORC1 is found in many developmental diseases, including autism spectrum disorder (ASD). Atypical reactivity to sensory stimuli is often found in patients with ASD. The most frequent hereditary cause of ASD is Tuberous Sclerosis Complex (TSC), in which inactivating mutations in the TSC1 or TSC2 genes result in hyperactivation of the mTORC1 pathway. We have discovered that the zebrafish model of TSC, tsc2vu242/vu242 mutants lack light preference, a behavior requiring integration of multiple sensory inputs. Here, we show that the lack of light preference in tsc2vu242/vu242 zebrafish is caused by aberrant sensory integration of light stimuli in the left dorsal habenula. Single-cell calcium imaging analysis revealed that tsc2vu242/vu242 fish showed impaired function of the left dorsal habenula, in which neurons exhibited higher activity and lacked habituation to the light stimuli resulting in atypical response to light. Lack of light-preference behavior and abnormal neuronal activity in the left dorsal habenula were rescued by rapamycin, indicating that hyperactive mTorC1 causes aberrant habenula function and impaired sensory integration resulting in lack of light preference. Our results link sensory integration deficits seen in TSC patients suffering from ASD with hyperactive mTORC1 and suggest that mTORC1 hyperactivity contributes to atypical reactivity to sensory stimuli in ASD.