Mini Review Open Access
Volume 3 | Issue 3 | DOI: https://doi.org/10.33696/Neurol.3.064

Neuroinflammation and Microglial Polarity: Sirolimus Shifts Microglial Polarity to M2 phenotype in a Mouse Model of Tuberous Sclerosis Complex

  • 1Department of Neurocutaneous Medicine, Division of Health Sciences, Graduate School of Medicine, Osaka University, 2-1 Yamada-oka, Suita, Osaka 565-0871, Japan
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Corresponding Author

Mari Wataya-Kaneda; mkaneda@sahs.med.osaka-u.ac.jp

Received Date: October 11, 2022

Accepted Date: December 05, 2022


Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome characterized by systemic hamartomas, including skin and neural symptoms. Many patients exhibit epilepsy, intellectual disability, autism, and other behavioral and neuropsychiatric symptoms, referred to as TSCassociated neuropsychiatric disorders (TAND). TSC involves the overactivation of the mechanistic target of rapamycin (mTOR), specifically mTOR complex 1 (mTORC1). Therefore, mTORC1 inhibitors effectively treat brain, kidney, lung, and skin hamartomas in TSC. However, the effect of mTORC1 inhibitors on neurological symptoms in patients with TSC remains unclear, despite reports of mTORC1 inhibitors improving epilepsy, behavioral disorders, and learning disabilities in animal models.

In our study, we revealed that MITF-specific TSC2 conditional knockout mice (TSC2 cKO) exhibit epilepsy and TAND phenotypes. Furthermore, mTORC1 inhibitor sirolimus treatment ameliorated epilepsy and some TAND symptoms in TSC2 cKO mice. Neurodegeneration was observed in the brain regions responsible for these symptoms. Neuroinflammation caused by the M1 phenotype of microglia is one of the factors contributing to neurodegeneration. In our study, microglia shifted to the anti-inflammatory M2 phenotype when TSC2 cKO mice were treated with sirolimus. Hyperactivity of mTORC1 inhibits autophagy, and increased autophagy activity polarizes microglia to the M2 phenotype. One of the possible mechanisms by which sirolimus can change microglial polarity is by inhibiting mTORC1 activity, which increases autophagy activity. In addition, sirolimus, which shifts microglial polarity to anti-inflammatory, may effectively treat TSC and other neurodegenerative diseases.


mTORC1 inhibitor, Sirolimus, Tuberous sclerosis complex, Microglia polarity, TSC-associated neuropsychiatric disorders, Epilepsy, Neuroinflammation

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