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Open Access 01-12-2024 | Tuberous Sclerosis | Research

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

Authors: Oak Z. Chi, Xia Liu, Harvey Fortus, Guy Werlen, Estela Jacinto, Harvey R. Weiss

Published in: NeuroMolecular Medicine | Issue 1/2024

Abstract

The manifestations of tuberous sclerosis complex (TSC) in humans include epilepsy, autism spectrum disorders (ASD) and intellectual disability. Previous studies suggested the linkage of TSC to altered cerebral blood flow and metabolic dysfunction. We previously reported a significant elevation in cerebral blood flow in an animal model of TSC and autism of young Eker rats. Inhibition of the mammalian target of rapamycin (mTOR) by rapamycin could restore normal oxygen consumption and cerebral blood flow. In this study, we investigated whether inhibiting a component of the mTOR signaling pathway, p70 ribosomal S6 kinase (S6K1), would yield comparable effects. Control Long Evans and Eker rats were divided into vehicle and PF-4708671 (S6K1 inhibitor, 75 mg/kg for 1 h) treated groups. Cerebral regional blood flow (¹⁴C-iodoantipyrine) was determined in isoflurane anesthetized rats. We found significantly increased basal cortical (+ 32%) and hippocampal (+ 15%) blood flow in the Eker rats. PF-4708671 significantly lowered regional blood flow in the cortex and hippocampus of the Eker rats. PF-4708671 did not significantly lower blood flow in these regions in the control Long Evans rats. Phosphorylation of S6-Ser240/244 and Akt-Ser473 was moderately decreased in Eker rats but only the latter reached statistical significance upon PF-4708671 treatment. Our findings suggest that moderate inhibition of S6K1 with PF-4708671 helps to restore normal cortical blood flow in Eker rats and that this information might have therapeutic potential in tuberous sclerosis complex and autism.

Aryal, S., Longo, F., & Klann, E. (2021). Genetic removal of p70 S6K1 corrects coding sequence length-dependent alterations in mRNA translation in fragile X syndrome mice. Proceedings of the National Academy of Sciences of the United States of America, 118(18), e2001681118. https://doi.org/10.1073/pnas.2001681118CrossRefPubMedPubMedCentral

Bassetti, D., Luhmann, H. J., & Kirischuk, S. (2021). Effects of mutations in TSC genes on neurodevelopment and synaptic transmission. International Journal of Molecular Sciences, 22(14), 7273. https://doi.org/10.3390/ijms22147273CrossRefPubMedPubMedCentral

Benjamin, D., Colombi, M., Moroni, C., & Hall, M. N. (2011). Rapamycin passes the torch: A new generation of mTOR inhibitors. Nature Reviews Drug Discovery, 10(11), 868–880. https://doi.org/10.1038/nrd3531CrossRefPubMed

Bhattacharya, A., Mamcarz, M., Mullins, C., Choudhury, A., Boyle, R. G., Smith, D. G., Walker, D. W., & Klann, E. (2016). Targeting translation control with p70 S6 kinase 1 inhibitors to reverse phenotypes in fragile X syndrome mice. Neuropsychopharmacology, 41(8), 1991–2000. https://doi.org/10.1038/npp.2015.369CrossRefPubMedPubMedCentral

Bombardieri, R., Pinci, M., Moavero, R., Cerminara, C., & Curatolo, P. (2010). Early control of seizures improves long-term outcome in children with tuberous sclerosis complex. European Journal of Paediatric Neurology, 14(2), 146–149. https://doi.org/10.1016/j.ejpn.2009.03.003CrossRefPubMed

Cavalheiro, S., da Costa, M. D. S., & Richtmann, R. (2021). Everolimus as a possible prenatal treatment of in utero diagnosed subependymal lesions in tuberous sclerosis complex: A case report. Child’s Nervous System, 37(12), 3897–3899. https://doi.org/10.1007/s00381-021-05218-4CrossRefPubMed

Chi, O. Z., Wu, C.-C., Liu, X., Rah, K. H., Jacinto, E., & Weiss, H. R. (2015). Restoration of normal cerebral oxygen consumption with rapamycin treatment in a rat model of autism-tuberous sclerosis. Neuromolecular Medicine, 17(3), 305–313. https://doi.org/10.1007/s12017-015-8359-5CrossRefPubMedPubMedCentral

Curatolo, P., Scheper, M., Emberti Gialloreti, L., Specchio, N., & Aronica, E. (2023). Is tuberous sclerosis complex-associated autism a preventable and treatable disorder? World Journal of Pediatrics. https://doi.org/10.1007/s12519-023-00762-2CrossRefPubMed

Curatolo, P., Specchio, N., & Aronica, E. (2022). Advances in the genetics and neuropathology of tuberous sclerosis complex: Edging closer to targeted therapy. The Lancet Neurology, 21(9), 843–856. https://doi.org/10.1016/S1474-4422(22)00213-7CrossRefPubMed

Czapski, G. A., Babiec, L., Jęśko, H., Gąssowska-Dobrowolska, M., Cieślik, M., Matuszewska, M., Frontczak-Baniewicz, M., Zajdel, K., & Adamczyk, A. (2021). Synaptic alterations in a transgenic model of tuberous sclerosis complex: Relevance to autism spectrum disorders. International Journal of Molecular Sciences, 22(18), 10058. https://doi.org/10.3390/ijms221810058CrossRefPubMedPubMedCentral

de Vries, P. J. (2010). Targeted treatments for cognitive and neurodevelopmental disorders in tuberous sclerosis complex. Neurotherapeutics, 7(3), 275–282. https://doi.org/10.1016/j.nurt.2010.05.001CrossRefPubMedPubMedCentral

Ehninger, D., Han, S., Shilyansky, C., Zhou, Y., Li, W., Kwiatkowski, D. J., Ramesh, V., & Silva, A. J. (2008). Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis. Nature Medicine, 14(8), 843–848. https://doi.org/10.1038/nm1788CrossRefPubMedPubMedCentral

Franz, D. N., Lawson, J. A., Yapici, Z., Ikeda, H., Polster, T., Nabbout, R., & French, J. A. (2021). Adjunctive everolimus therapy for tuberous sclerosis complex-associated refractory seizures: Results from the postextension phase of EXIST-3. Epilepsia, 62(12), 3029–3041. https://doi.org/10.1111/epi.17099CrossRefPubMed

French, J. A., Lawson, J. A., Yapici, Z., Ikeda, H., Polster, T., Nabbout, R., & Franz, D. N. (2016). Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): A phase 3, randomised, double-blind, placebo-controlled study. The Lancet (London, England), 388(10056), 2153–2163. https://doi.org/10.1016/S0140-6736(16)31419-2CrossRefPubMed

Ganesan, H., Balasubramanian, V., Iyer, M., Venugopal, A., Subramaniam, M. D., Cho, S.-G., & Vellingiri, B. (2019). mTOR signalling pathway: A root cause for idiopathic autism? BMB Reports, 52(7), 424–433. https://doi.org/10.5483/BMBRep.2019.52.7.137CrossRefPubMedPubMedCentral

Ganesh, S. K., & Subathra Devi, C. (2023). Molecular and therapeutic insights of rapamycin: A multi-faceted drug from Streptomyces hygroscopicus. Molecular Biology Reports, 50(4), 3815–3833. https://doi.org/10.1007/s11033-023-08283-xCrossRefPubMedPubMedCentral

Gkogkas, C. G., Khoutorsky, A., Ran, I., Rampakakis, E., Nevarko, T., Weatherill, D. B., & Sonenberg, N. (2013). Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature, 493(7432), 371–377. https://doi.org/10.1038/nature11628CrossRefPubMed

Habib, S. L. (2010). Tuberous sclerosis complex and DNA repair. Advances in Experimental Medicine and Biology, 685, 84–94. https://doi.org/10.1007/978-1-4419-6448-9_8CrossRefPubMed

Harrington, L. S., Findlay, G. M., & Lamb, R. F. (2005). Restraining PI3K: MTOR signalling goes back to the membrane. Trends in Biochemical Sciences, 30(1), 35–42. https://doi.org/10.1016/j.tibs.2004.11.003CrossRefPubMed

Hayashi, I., Aoki, Y., Ushikubo, H., Asano, D., Mori, A., Sakamoto, K., Nakahara, T., & Ishii, K. (2016). Protective effects of PF-4708671 against N-methyl-d-aspartic acid-induced retinal damage in rats. Fundamental & Clinical Pharmacology, 30(6), 529–536. https://doi.org/10.1111/fcp.12216CrossRef

Henske, E. P., Jóźwiak, S., Kingswood, J. C., Sampson, J. R., & Thiele, E. A. (2016). Tuberous sclerosis complex. Nature Reviews Disease Primers, 2, 16035. https://doi.org/10.1038/nrdp.2016.35CrossRefPubMed

Hosking, S. L., Roff Hilton, E. J., Embleton, S. J., & Gupta, A. K. (2003). Epilepsy patients treated with vigabatrin exhibit reduced ocular blood flow. The British Journal of Ophthalmology, 87(1), 96–100. https://doi.org/10.1136/bjo.87.1.96CrossRefPubMedPubMedCentral

Huang, J., & Manning, B. D. (2008). The TSC1-TSC2 complex: A molecular switchboard controlling cell growth. The Biochemical Journal, 412(2), 179–190. https://doi.org/10.1042/BJ20080281CrossRefPubMed

Kelleher, R. J., & Bear, M. F. (2008). The autistic neuron: Troubled translation? Cell, 135(3), 401–406. https://doi.org/10.1016/j.cell.2008.10.017CrossRefPubMed

Koike-Kumagai, M., Fujimoto, M., & Wataya-Kaneda, M. (2022). Sirolimus relieves seizures and neuropsychiatric symptoms via changes of microglial polarity in tuberous sclerosis complex model mice. Neuropharmacology, 218, 109203. https://doi.org/10.1016/j.neuropharm.2022.109203CrossRefPubMed

Krueger, D. A., Capal, J. K., Curatolo, P., Devinsky, O., Ess, K., Tzadok, M., … & TSCure Research Group. (2018). Short-term safety of mTOR inhibitors in infants and very young children with tuberous sclerosis complex (TSC): Multicentre clinical experience. European Journal of Paediatric Neurology, 22(6), 1066–1073. https://doi.org/10.1016/j.ejpn.2018.06.007CrossRef

Kútna, V., Uttl, L., Waltereit, R., Krištofiková, Z., Kaping, D., Petrásek, T., Hoschl, C., & Ovsepian, S. V. (2020). Tuberous sclerosis (tsc2+/-) model Eker rats reveals extensive neuronal loss with microglial invasion and vascular remodeling related to brain neoplasia. Neurotherapeutics, 17(1), 329–339. https://doi.org/10.1007/s13311-019-00812-6CrossRefPubMed

Li, J., Kim, S. G., & Blenis, J. (2014). Rapamycin: One drug, many effects. Cell Metabolism, 19(3), 373–379. https://doi.org/10.1016/j.cmet.2014.01.001CrossRefPubMedPubMedCentral

Magaway, C., Kim, E., & Jacinto, E. (2019). Targeting mTOR and metabolism in cancer: Lessons and innovations. Cells, 8(12), 1584. https://doi.org/10.3390/cells8121584CrossRefPubMedPubMedCentral

Mizuguchi, M., Ohsawa, M., Kashii, H., & Sato, A. (2021). Brain symptoms of tuberous sclerosis complex: Pathogenesis and treatment. International Journal of Molecular Sciences, 22(13), 6677. https://doi.org/10.3390/ijms22136677CrossRefPubMedPubMedCentral

Oh, W. J., & Jacinto, E. (2011). mTOR complex 2 signaling and functions. Cell Cycle, 10(14), 2305–2316. https://doi.org/10.4161/cc.10.14.16586CrossRefPubMedPubMedCentral

Pagani, M., Barsotti, N., Bertero, A., Trakoshis, S., Ulysse, L., Locarno, A., & Gozzi, A. (2021). mTOR-related synaptic pathology causes autism spectrum disorder-associated functional hyperconnectivity. Nature Communications, 12(1), 6084. https://doi.org/10.1038/s41467-021-26131-zCrossRefPubMedPubMedCentral

Pearce, L. R., Alton, G. R., Richter, D. T., Kath, J. C., Lingardo, L., Chapman, J., Hwang, C., & Alessi, D. R. (2010). Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1). The Biochemical Journal, 431(2), 245–255. https://doi.org/10.1042/BJ20101024CrossRefPubMed

Peters, J. M., Prohl, A., Kapur, K., Nath, A., Scherrer, B., Clancy, S., Prabhu, S. P., Sahin, M., Franz, D. N., Warfield, S. K., & Krueger, D. A. (2019). Longitudinal effects of everolimus on white matter diffusion in tuberous sclerosis complex. Pediatric Neurology, 90, 24–30. https://doi.org/10.1016/j.pediatrneurol.2018.10.005CrossRefPubMed

Peters, J. M., Taquet, M., Prohl, A. K., Scherrer, B., Van Eeghen, A. M., Prabhu, S. P., Sahin, M., & Warfield, S. K. (2013). Diffusion tensor imaging and related techniques in tuberous sclerosis complex: Review and future directions. Future Neurology, 8(5), 583–597. https://doi.org/10.2217/fnl.13.37CrossRefPubMedPubMedCentral

Rubenstein, J. L. R., & Merzenich, M. M. (2003). Model of autism: Increased ratio of excitation/inhibition in key neural systems. Genes, Brain, and Behavior, 2(5), 255–267. https://doi.org/10.1034/j.1601-183x.2003.00037.xCrossRefPubMed

Rutten, C., Fillon, L., Kuchenbuch, M., Saitovitch, A., Boisgontier, J., Chemaly, N., & Boddaert, N. (2023). The longitudinal evolution of cerebral blood flow in children with tuberous sclerosis assessed by arterial spin labeling magnetic resonance imaging may be related to cognitive performance. European Radiology, 33(1), 196–206. https://doi.org/10.1007/s00330-022-09036-3CrossRefPubMed

Sarbassov, D. D., Ali, S. M., Sengupta, S., Sheen, J. H., Hsu, P. P., Bagley, A. F., Markhard, A. L., & Sabatini, D. M. (2006). Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Molecular Cell, 22(2), 159–168. https://doi.org/10.1016/j.molcel.2006.03.029CrossRefPubMed

Schneider, M., de Vries, P. J., Schönig, K., Rößner, V., & Waltereit, R. (2017). mTOR inhibitor reverses autistic-like social deficit behaviours in adult rats with both Tsc2 haploinsufficiency and developmental status epilepticus. European Archives of Psychiatry and Clinical Neuroscience, 267(5), 455–463. https://doi.org/10.1007/s00406-016-0703-8CrossRefPubMed

Sharma, A., & Mehan, S. (2021). Targeting PI3K-AKT/mTOR signaling in the prevention of autism. Neurochemistry International, 147, 105067. https://doi.org/10.1016/j.neuint.2021.105067CrossRefPubMed

Spanaki, M. V., Siegel, H., Kopylev, L., Fazilat, S., Dean, A., Liow, K., Ben-Menachem, E., Gaillard, W. D., & Theodore, W. H. (1999). The effect of vigabatrin (gamma-vinyl GABA) on cerebral blood flow and metabolism. Neurology, 53(7), 1518–1522. https://doi.org/10.1212/wnl.53.7.1518CrossRefPubMed

Specchio, N., Nabbout, R., Aronica, E., Auvin, S., Benvenuto, A., de Palma, L., & Curatolo, P. (2023). Updated clinical recommendations for the management of tuberous sclerosis complex associated epilepsy. European Journal of Paediatric Neurology, 47, 25–34. https://doi.org/10.1016/j.ejpn.2023.08.005CrossRefPubMed

Srivastava, I. N., Shperdheja, J., Baybis, M., Ferguson, T., & Crino, P. B. (2016). mTOR pathway inhibition prevents neuroinflammation and neuronal death in a mouse model of cerebral palsy. Neurobiology of Disease, 85, 144–154. https://doi.org/10.1016/j.nbd.2015.10.001CrossRefPubMed

Szwed, A., Kim, E., & Jacinto, E. (2021). Regulation and metabolic functions of mTORC1 and mTORC2. Physiological Reviews, 101(3), 1371–1426. https://doi.org/10.1152/physrev.00026.2020CrossRefPubMedPubMedCentral

Talos, D. M., Sun, H., Kosaras, B., Joseph, A., Folkerth, R. D., Poduri, A., Madsen, J. R., Black, P. M., & Jensen, F. E. (2012). Altered inhibition in tuberous sclerosis and type IIb cortical dysplasia. Annals of Neurology, 71(4), 539–551. https://doi.org/10.1002/ana.22696CrossRefPubMedPubMedCentral

Tavares, M. R., Pavan, I. C. B., Amaral, C. L., Meneguello, L., Luchessi, A. D., & Simabuco, F. M. (2015). The S6K protein family in health and disease. Life Sciences, 131, 1–10. https://doi.org/10.1016/j.lfs.2015.03.001CrossRefPubMed

Tsai, P. T., Hull, C., Chu, Y., Greene-Colozzi, E., Sadowski, A. R., Leech, J. M., Steinberg, J., Crawley, J. N., Regehr, W. G., & Sahin, M. (2012). Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature, 488(7413), 647–651. https://doi.org/10.1038/nature11310CrossRefPubMedPubMedCentral

Waltereit, R., Japs, B., Schneider, M., de Vries, P. J., & Bartsch, D. (2011). Epilepsy and Tsc2 haploinsufficiency lead to autistic-like social deficit behaviors in rats. Behavior Genetics, 41(3), 364–372. https://doi.org/10.1007/s10519-010-9399-0CrossRefPubMed

Weiss, H. R., Liu, X., & Chi, O. Z. (2008). Cerebral O(2) consumption in young Eker rats, effects of GABA blockade: Implications for autism. International Journal of Developmental Neuroscience, 26(5), 517–521. https://doi.org/10.1016/j.ijdevneu.2008.01.002CrossRefPubMed

Weiss, H. R., Liu, X., Grewal, P., & Chi, O. Z. (2012). Reduced effect of stimulation of AMPA receptors on cerebral O₂ consumption in a rat model of autism. Neuropharmacology, 63(5), 837–841. https://doi.org/10.1016/j.neuropharm.2012.06.014CrossRefPubMed

Weiss, H. R., Liu, X., Hunter, C., & Chi, O. Z. (2009). Effects of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor blockade on increased cerebral O(2) consumption in Eker rats. Brain Research, 1294, 138–143. https://doi.org/10.1016/j.brainres.2009.08.022CrossRefPubMed

Weiss, H. R., Liu, X., Zhang, Q., & Chi, O. Z. (2007). Increased cerebral oxygen consumption in Eker rats and effects of N-methyl-D-aspartate blockade: Implications for autism. Journal of Neuroscience Research, 85(11), 2512–2517. https://doi.org/10.1002/jnr.21378CrossRefPubMed

Wenzel, H. J., Patel, L. S., Robbins, C. A., Emmi, A., Yeung, R. S., & Schwartzkroin, P. A. (2004). Morphology of cerebral lesions in the Eker rat model of tuberous sclerosis. Acta Neuropathologica, 108(2), 97–108. https://doi.org/10.1007/s00401-004-0865-8CrossRefPubMed

Winden, K. D., Ebrahimi-Fakhari, D., & Sahin, M. (2018). Abnormal mTOR activation in autism. Annual Review of Neuroscience, 41, 1–23. https://doi.org/10.1146/annurev-neuro-080317-061747CrossRefPubMed

Zeng, L.-H., Xu, L., Gutmann, D. H., & Wong, M. (2008). Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Annals of Neurology, 63(4), 444–453. https://doi.org/10.1002/ana.21331CrossRefPubMedPubMedCentral

Title: Inhibition of p70 Ribosomal S6 Kinase (S6K1) Reduces Cortical Blood Flow in a Rat Model of Autism-Tuberous Sclerosis
Authors: Oak Z. Chi
Xia Liu
Harvey Fortus
Guy Werlen
Estela Jacinto
Harvey R. Weiss
Publication date: 01-12-2024
Publisher: Springer US
Keywords: Tuberous Sclerosis
Autism Spectrum Disorder
Published in: NeuroMolecular Medicine / Issue 1/2024
Print ISSN: 1535-1084
Electronic ISSN: 1559-1174
DOI: https://doi.org/10.1007/s12017-024-08780-7

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

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