Sirolimus relieves seizures and neuropsychiatric symptoms via changes of microglial polarity in tuberous sclerosis complex model mice

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

“…Furthermore, this detailed behavioral analysis suggested that TSC2 cKO mice may be a useful model for TAND, as they exhibit epilepsy and multiple neuropsychiatric phenotypes: ADHD-like behavior, anxiety-like symptoms, ASD-like behavior, and significant impairment of spatial working memory [16]. Cre expression analysis also revealed that the olfactory bulb, piriform cortex, and hippocampus were the sites responsible for epilepsy and TAND in TSC2 cKO mice, and neurodegeneration occurred in these regions [16].…”

“…In TSC2 cKO olfactory bulb treated with sirolimus, microglial morphology was predominantly larger, and microglial process branching increased [16] (Figures 1A and 1B). Sirolimus treatment resulted in predominantly higher expressions of IL-10, Arg1, and CD206, which are expressed in the M2 phenotype (Figure 1C).…”

“…Our group generated TSC2 flox/flox , Mitf-Cre conditional knockout (TSC2 cKO) mice and performed a detailed behavioral analysis of the cKO mice [16]. These TSC2 cKO mice have been previously reported in our studies to significantly reduce skin pigmentation and exhibit spontaneous epilepsy [17,18].…”

“…We investigated the expression of P1 and P2 receptors on microglia because the microglia morphology in TSC2 cKO mice was significantly altered by sirolimus treatment (Figures 1A and 1B) [16]. In Figure 1C, color intensity depicts the expression levels of receptors and markers, with darker red and blue indicating higher and lower expression, respectively.…”

Inhibition of p70 Ribosomal S6 Kinase (S6K1) Reduces Cortical Blood Flow in a Rat Model of Autism-Tuberous Sclerosis

“…Since increased activation of mTORC1 could contribute to the manifestations of TSC such as epilepsy, intellectual disability and ASD, pharmacological inhibition of mTORC1 may be effective in preventing and reducing TSC associated neuropathological symptoms (Mizuguchi et al, 2021 ; Winden et al, 2018 ). Rapamycin and its second generation everolimus have been shown to reduce seizure susceptibility and autism-like behavior in several animal models of TSC (de Vries, 2010 ; Ehninger et al, 2008 ; Koike-Kumagai et al, 2022 ; Talos et al, 2012 ; Tsai et al, 2012 ; Zeng et al, 2008 ). Rapamycin has been tested in humans with ASD, with some potential benefit (Cavalheiro et al, 2021 ; Franz et al, 2021 ; French et al, 2016 ; Krueger et al, 2018 ; Mizuguchi et al, 2021 ; Winden et al, 2018 ).…”