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Restoration of Normal Cerebral Oxygen Consumption with Rapamycin Treatment in a Rat Model of Autism–Tuberous Sclerosis

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Abstract

Tuberous sclerosis (TSC) is associated with autism spectrum disorders and has been linked to metabolic dysfunction and unrestrained signaling of the mammalian target of rapamycin (mTOR). Inhibition of mTOR by rapamycin can mitigate some of the phenotypic abnormalities associated with TSC and autism, but whether this is due to the mTOR-related function in energy metabolism remains to be elucidated. In young Eker rats, an animal model of TSC and autism, which harbors a germ line heterozygous Tsc2 mutation, we previously reported that cerebral oxygen consumption was pronouncedly elevated. Young (4 weeks) male control Long–Evans and Eker rats were divided into control and rapamycin-treated (20 mg/kg once daily for 2 days) animals. Cerebral regional blood flow (14C-iodoantipyrine) and O2 consumption (cryomicrospectrophotometry) were determined in isoflurane-anesthetized rats. We found significantly increased basal O2 consumption in the cortex (8.7 ± 1.5 ml O2/min/100 g Eker vs. 2.7 ± 0.2 control), hippocampus, pons and cerebellum. Regional cerebral blood flow and cerebral O2 extractions were also elevated in all brain regions. Rapamycin had no significant effect on O2 consumption in any brain region of the control rats, but significantly reduced consumption in the cortex (4.1 ± 0.3) and all other examined regions of the Eker rats. Phosphorylation of mTOR and S6K1 was similar in the two groups and equally reduced by rapamycin. Thus, a rapamycin-sensitive, mTOR-dependent but S6K1-independent, signal led to enhanced oxidative metabolism in the Eker brain. We found decreased Akt phosphorylation in Eker but not Long–Evans rat brains, suggesting that this may be related to the increased cerebral O2 consumption in the Eker rat. Our findings suggest that rapamycin targeting of Akt to restore normal cerebral metabolism could have therapeutic potential in tuberous sclerosis and autism.

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Acknowledgments

This work was supported, in part, by the NIH (GM079176) (E.J.) and the New Jersey Governor’s Council for Medical Research and Treatment of Autism (H.R.W.).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, 08854, USA

    Chang-Chih Wu & Estela Jacinto

  2. Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, 675 Hoes Lane West, Piscataway, NJ, 08854, USA

    Harvey R. Weiss

  3. Department of Anesthesiology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, 08854, USA

    Oak Z. Chi, Xia Liu & Kang H. Rah

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  1. Oak Z. Chi
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  2. Chang-Chih Wu
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Correspondence to Harvey R. Weiss.

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Chi, O.Z., Wu, CC., Liu, X. et al. Restoration of Normal Cerebral Oxygen Consumption with Rapamycin Treatment in a Rat Model of Autism–Tuberous Sclerosis. Neuromol Med 17, 305–313 (2015). https://doi.org/10.1007/s12017-015-8359-5

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