mTOR inhibitor reverses autistic-like social deficit behaviours in adult rats with both Tsc2 haploinsufficiency and developmental status epilepticus

  • Miriam Schneider
  • Petrus J. de Vries
  • Kai Schönig
  • Veit Rößner
  • Robert Waltereit
Original Paper

Abstract

Epilepsy is a major risk factor for autism spectrum disorder (ASD) and complicates clinical manifestations and management of ASD significantly. Tuberous sclerosis complex (TSC), caused by TSC1 or TSC2 mutations, is one of the medical conditions most commonly associated with ASD and has become an important model to examine molecular pathways associated with ASD. Previous research showed reversal of autism-like social deficits in Tsc1+/ and Tsc2+/ mouse models by mammalian target of rapamycin (mTOR) inhibitors. However, at least 70 % of individuals with TSC also have epilepsy, known to complicate the severity and treatment responsiveness of the behavioural phenotype. No previous study has examined the impact of seizures on neurocognitive reversal by mTOR inhibitors. Adult Tsc2+/ (Eker)-rats express social deficits similar to Tsc2+/ mice, with additive social deficits from developmental status epilepticus (DSE). DSE was induced by intraperitoneal injection with kainic acid at post-natal days P7 and P14 (n = 12). The experimental group that modelled TSC pathology carried the Tsc2+/− (Eker)-mutation and was challenged with DSE. The wild-type controls had not received DSE (n = 10). Four-month-old animals were analysed for social behaviour (T1), then treated three times during 1 week with 1 mg/kg everolimus and finally retested in the post-treatment behavioural analysis (T2). In the experimental group, both social interaction and social cognition were impaired at T1. After treatment at T2, behaviour in the experimental group was indistinguishable from controls. The mTOR inhibitor, everolimus, reversed social deficit behaviours in the Tsc2 haploinsufficiency plus DSE animal model to control levels.

Keywords

Animal model Autism spectrum disorder Everolimus Experimental therapy Social cognition Tuberous sclerosis complex 

References

  1. 1.
    Baird G, Simonoff E, Pickles A et al (2006) Prevalence of disorders of the autism spectrum in a population cohort of children in South Thames: the Special Needs and Autism Project (SNAP). Lancet 368:210–215CrossRefPubMedGoogle Scholar
  2. 2.
    Tuchman R, Rapin I (2002) Epilepsy in autism. Lancet Neurol 1:352–358CrossRefPubMedGoogle Scholar
  3. 3.
    Curatolo P, Moavero R, de Vries PJ (2015) Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol 14:733–745. doi:10.1016/S1474-4422(15)00069-1 CrossRefPubMedGoogle Scholar
  4. 4.
    Ehninger D, Han S, Shilyansky C et al (2008) Reversal of learning deficits in a Tsc2+/ mouse model of tuberous sclerosis. Nat Med 14:843–848CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Tsai PT, Hull C, Chu Y et al (2013) Autistic-like behavior and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature 488:647–651CrossRefGoogle Scholar
  6. 6.
    Sato A, Kasai S, Kobayashi T et al (2012) Rapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex. Nat Commun 3:1292. doi:10.1038/ncomms2295 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Riikonen R, Amnell G (1981) Psychiatric disorders in children with earlier infantile spasms. Dev Med Child Neurol 23:747–760CrossRefPubMedGoogle Scholar
  8. 8.
    Primec ZR, Stare J, Neubauer D (2006) The risk of lower mental outcome in infantile spasms increases after three weeks of hypsarrhythmia duration. Epilepsia 47:2202–2205CrossRefPubMedGoogle Scholar
  9. 9.
    Goh S, Kwiatkowski DJ, Dorer DJ, Thiele EA (2005) Infantile spasms and intellectual outcomes in children with tuberous sclerosis complex. Neurology 65:235–238CrossRefPubMedGoogle Scholar
  10. 10.
    O’Callaghan FJ, Harris T, Joinson C et al (2004) The relation of infantile spasms, tubers, and intelligence in tuberous sclerosis complex. Arch Dis Child 89:530–533CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Workman AD, Charvet CJ, Clancy B et al (2013) Modeling transformations of neurodevelopmental sequences across mammalian species. J Neurosci 33:7368–7383. doi:10.1523/JNEUROSCI.5746-12.2013 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Lynch M, Sayin U, Bownds J et al (2000) Long-term consequences of early postnatal seizures on hippocampal learning and plasticity. Eur J Neurosci 12:2252–2264CrossRefPubMedGoogle Scholar
  13. 13.
    Sayin U, Sutula TP, Stafstrom CE (2004) Seizures in the developing brain cause adverse long-term effects on spatial learning and anxiety. Epilepsia 45:1539–1548CrossRefPubMedGoogle Scholar
  14. 14.
    Ikonomidou C, Bosch F, Miksa M et al (1999) Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 283:70–74CrossRefPubMedGoogle Scholar
  15. 15.
    Lim AL, Taylor DA, Malone DT (2012) Consequences of early life MK-801 administration: long-term behavioural effects and relevance to schizophrenia research. Behav Brain Res 227:276–286. doi:10.1016/j.bbr.2011.10.052 CrossRefPubMedGoogle Scholar
  16. 16.
    von der Brelie C, Waltereit R, Zhang L et al (2006) Impaired synaptic plasticity in a rat model of tuberous sclerosis. Eur J Neurosci 23:686–692. doi:10.1111/j.1460-9568.2006.04594.x CrossRefPubMedGoogle Scholar
  17. 17.
    Waltereit R, Welzl H, Dichgans J et al (2006) Enhanced episodic-like memory and kindling epilepsy in a rat model of tuberous sclerosis. J Neurochem 96:407–413CrossRefPubMedGoogle Scholar
  18. 18.
    Waltereit R, Japs B, Schneider M et al (2011) Epilepsy and Tsc2 haploinsufficiency lead to autistic-like social deficit behaviors in rats. Behav Genet 41:364–372CrossRefPubMedGoogle Scholar
  19. 19.
    Kenerson HL, Aicher LD, True LD, Yeung RS (2002) Activated mammalian target of rapamycin pathway in the pathogenesis of tuberous sclerosis complex renal tumors. Cancer Res 62:5645–5650PubMedGoogle Scholar
  20. 20.
    Kenerson H, Dundon TA, Yeung RS (2005) Effects of rapamycin in the Eker rat model of tuberous sclerosis complex. Pediatr Res 57:67–75. doi:10.1203/01.PDR.0000147727.78571.07 CrossRefPubMedGoogle Scholar
  21. 21.
    O’Reilly T, McSheehy PMJ, Kawai R et al (2009) Comparative pharmacokinetics of RAD001 (everolimus) in normal and tumor-bearing rodents. Cancer Chemother Pharmacol 65:625–639CrossRefPubMedGoogle Scholar
  22. 22.
    Rennebeck G, Kleymenova EV, Anderson R et al (1998) Loss of function of the tuberous sclerosis 2 tumor suppressor gene results in embryonic lethality characterized by disrupted neuroepithelial growth and development. Proc Natl Acad Sci USA 95:15629–15634CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Schneider M, Schomig E, Leweke FM (2008) Acute and chronic cannabinoid treatment differentially affects recognition memory and social behavior in pubertal and adult rats. Addict Biol 13:345–357CrossRefPubMedGoogle Scholar
  24. 24.
    Meikle L, Pollizzi K, Egnor A et al (2008) Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function. J Neurosci 28:5422–5432. doi:10.1523/JNEUROSCI.0955-08.2008 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Rutter M, Bishop D, Pine D et al (2010) Rutter’s child and adolescent psychiatry, 5th edn. Wiley-Blackwell, HobokenGoogle Scholar
  26. 26.
    Ishii R, Wataya-Kaneda M, Canuet L et al (2015) Everolimus improves behavioral deficits in a patient with autism associated with tuberous sclerosis: a case report. Neuropsychiatr Electrophysiol 1:6. doi:10.1186/s40810-015-0004-x CrossRefGoogle Scholar
  27. 27.
    Chu-Shore CJ, Major P, Camposano S et al (2010) The natural history of epilepsy in tuberous sclerosis complex. Epilepsia 51:1236–1241. doi:10.1111/j.1528-1167.2009.02474.x CrossRefPubMedGoogle Scholar
  28. 28.
    Deykin EY, MacMahon B (1979) The incidence of seizures among children with autistic symptoms. Am J Psychiatry 136:1310–1312CrossRefPubMedGoogle Scholar
  29. 29.
    Woolfenden S, Sarkozy V, Ridley G et al (2012) A systematic review of two outcomes in autism spectrum disorder—epilepsy and mortality. Dev Med Child Neurol 54:306–312. doi:10.1111/j.1469-8749.2012.04223.x CrossRefPubMedGoogle Scholar
  30. 30.
    Tuchman R, Cuccaro M (2011) Epilepsy and autism: neurodevelopmental perspective. Curr Neurol Neurosci Rep 11:428–434. doi:10.1007/s11910-011-0195-x CrossRefPubMedGoogle Scholar
  31. 31.
    Smalley SL (1998) Autism and tuberous sclerosis. J Autism Dev Disord 28:407–414CrossRefPubMedGoogle Scholar
  32. 32.
    Gomez MR, Sampson JR, Whittemore VH (1999) The tuberous sclerosis complex. Oxford University Press, New YorkGoogle Scholar
  33. 33.
    de Vries PJ, Prather PA (2007) The tuberous sclerosis complex. N Engl J Med 356:92CrossRefPubMedGoogle Scholar
  34. 34.
    Zeng L-H, Xu L, Gutmann DH, Wong M (2008) Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol 63:444–453. doi:10.1002/ana.21331 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Krueger DA, Wilfong AA, Holland-Bouley K et al (2013) Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Ann Neurol 74:679–687. doi:10.1002/ana.23960 CrossRefPubMedGoogle Scholar
  36. 36.
    Wong M (2013) A critical review of mTOR inhibitors and epilepsy: from basic science to clinical trials. Expert Rev Neurother 13:657–669. doi:10.1586/ern.13.48 CrossRefPubMedGoogle Scholar
  37. 37.
    de Vries PJ, Howe CJ (2007) The tuberous sclerosis complex proteins—a GRIPP on cognition and neurodevelopment. Trends Mol Med 13:319–326CrossRefPubMedGoogle Scholar
  38. 38.
    Ehninger D, de Vries PJ, Silva AJ (2009) From mTOR to cognition: molecular and cellular mechanisms of cognitive impairments in tuberous sclerosis. J Intellect Disabil Res 53:838–851CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Napolioni V, Moavero R, Curatolo P (2009) Recent advances in neurobiology of Tuberous Sclerosis Complex. Brain Dev 31:104–113. doi:10.1016/j.braindev.2008.09.013 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Research Group Developmental Neuropsychopharmacology, Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty MannheimUniversity of HeidelbergMannheimGermany
  2. 2.Division of Child and Adolescent PsychiatryUniversity of Cape TownCape TownSouth Africa
  3. 3.Department of Molecular Biology, Central Institute of Mental Health, Medical Faculty MannheimUniversity of HeidelbergMannheimGermany
  4. 4.Department of Child and Adolescent Psychiatry, University Hospital Carl Gustav Carus, Faculty of MedicineTechnical University of DresdenDresdenGermany
  5. 5.Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty MannheimUniversity of HeidelbergMannheimGermany

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