PMID- 26048361 OWN - NLM STAT- MEDLINE DCOM- 20160520 LR - 20211203 IS - 1559-1174 (Electronic) IS - 1535-1084 (Print) IS - 1535-1084 (Linking) VI - 17 IP - 3 DP - 2015 Sep TI - Restoration of Normal Cerebral Oxygen Consumption with Rapamycin Treatment in a Rat Model of Autism-Tuberous Sclerosis. PG - 305-13 LID - 10.1007/s12017-015-8359-5 [doi] AB - 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 ((14)C-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. FAU - Chi, Oak Z AU - Chi OZ AD - Department of Anesthesiology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, 08854, USA. FAU - Wu, Chang-Chih AU - Wu CC FAU - Liu, Xia AU - Liu X FAU - Rah, Kang H AU - Rah KH FAU - Jacinto, Estela AU - Jacinto E FAU - Weiss, Harvey R AU - Weiss HR LA - eng GR - R01 GM079176/GM/NIGMS NIH HHS/United States GR - GM079176/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20150606 PL - United States TA - Neuromolecular Med JT - Neuromolecular medicine JID - 101135365 RN - 0 (Nerve Tissue Proteins) RN - 0 (TSC2 protein, human) RN - 0 (Tsc2 protein, rat) RN - 0 (Tuberous Sclerosis Complex 2 Protein) RN - 0 (Tumor Suppressor Proteins) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (Akt1 protein, rat) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases) RN - EC 2.7.11.1 (Rps6kb1 protein, rat) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - S88TT14065 (Oxygen) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Autism Spectrum Disorder/*drug therapy/metabolism MH - Brain/*drug effects/metabolism MH - Cerebrovascular Circulation/drug effects MH - Disease Models, Animal MH - Heterozygote MH - Male MH - Nerve Tissue Proteins/antagonists & inhibitors/metabolism MH - Organ Specificity MH - Oxygen/blood MH - Oxygen Consumption/*drug effects MH - Phosphorylation/drug effects MH - Protein Processing, Post-Translational/drug effects MH - Proto-Oncogene Proteins c-akt/metabolism MH - Rats MH - Rats, Long-Evans MH - Rats, Mutant Strains MH - Ribosomal Protein S6 Kinases/metabolism MH - Sirolimus/pharmacology/*therapeutic use MH - TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism MH - Tuberous Sclerosis/*drug therapy/genetics/metabolism MH - Tuberous Sclerosis Complex 2 Protein MH - Tumor Suppressor Proteins/genetics PMC - PMC4888058 MID - NIHMS787844 COIS- Conflict of interest None. EDAT- 2015/06/07 06:00 MHDA- 2016/05/21 06:00 PMCR- 2016/06/01 CRDT- 2015/06/07 06:00 PHST- 2015/03/06 00:00 [received] PHST- 2015/05/30 00:00 [accepted] PHST- 2015/06/07 06:00 [entrez] PHST- 2015/06/07 06:00 [pubmed] PHST- 2016/05/21 06:00 [medline] PHST- 2016/06/01 00:00 [pmc-release] AID - 10.1007/s12017-015-8359-5 [doi] PST - ppublish SO - Neuromolecular Med. 2015 Sep;17(3):305-13. doi: 10.1007/s12017-015-8359-5. Epub 2015 Jun 6.