Conditional knockout of Tsc1 in RORγt-expressing cells induces brain damage and early death in mice

Background Tuberous sclerosis complex 1 (Tsc1) is known to regulate the development and function of various cell types, and ROR gamma t is a critical transcription factor in the immune system. However, whether Tsc1 participates in regulating ROR gamma t-expressing cells remains unknown. Methods We generated a mouse model in which Tsc1 was conditionally deleted from ROR gamma t-expressing cells (Tsc1(ROR gamma t)) to study the role of ROR gamma t-expressing cells with Tsc1 deficiency in brain homeostasis. Results Type 3 innate lymphoid cells (ILC3s) in Tsc1(ROR gamma t) mice displayed normal development and function, and the mice showed normal Th17 cell differentiation. However, Tsc1(ROR gamma t) mice exhibited spontaneous tonic-clonic seizures and died between 4 and 6 weeks after birth. At the age of 4 weeks, mice in which Tsc1 was specifically knocked out in ROR gamma t-expressing cells had cortical neuron defects and hippocampal structural abnormalities. Notably, over-activation of neurons and astrogliosis were observed in the cortex and hippocampus of Tsc1(ROR gamma t) mice. Moreover, expression of the gamma-amino butyric acid (GABA) receptor in the brains of Tsc1(ROR gamma t) mice was decreased, and GABA supplementation prolonged the lifespan of the mice to some extent. Further experiments revealed the presence of a group of rare ROR gamma t-expressing cells with high metabolic activity in the mouse brain. Conclusions Our study verifies the critical role of previously unnoticed ROR gamma t-expressing cells in the brain and demonstrates that the Tsc1 signaling pathway in ROR gamma t-expressing cells is important for maintaining brain homeostasis.