Loss of Tsc2 in Purkinje cells is associated with autistic-like behavior in a mouse model of tuberous sclerosis complex

Neurobiology of Disease

Volumn 51, Issue , 2013, Pages 93-103

  Reith, R Michelle ^a   McKenna, James ^b   Wu, Henry ^c   Hashmi, S Shahrukh ^d   Cho, Seo Hee ^e   Dash, Pramod K ^f   Gambello, Michael J ^b  

^a UT Health   (United States)

^b EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c Division of Cardiology   (United States)

^d Division of Medical Genetics   (United States)

^e TEMPLE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^f NONE   (United States)

Author keywords

Autism; Mouse; Purkinje cell; Rapamycin; Repetitive behavior; Social; Tsc2; Tuberous sclerosis

Indexed keywords

RAPAMYCIN; TUBERIN;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANXIETY; ARTICLE; AUTISM; CEREBELLUM; COMPULSION; CONTROLLED STUDY; FEMALE; HAPLOINSUFFICIENCY; MALE; MOUSE; NERVE CELL DEGENERATION; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; PURKINJE CELL; SOCIAL BEHAVIOR; SOCIAL DISABILITY; SOCIAL INTERACTION; SPATIAL LEARNING; SPATIAL MEMORY; TUBEROUS SCLEROSIS;

ANIMALS; BEHAVIOR, ANIMAL; CHILD; CHILD DEVELOPMENT DISORDERS, PERVASIVE; DISEASE MODELS, ANIMAL; FEMALE; HUMANS; IMMUNOHISTOCHEMISTRY; MALE; MICE; PURKINJE CELLS; TUBEROUS SCLEROSIS; TUMOR SUPPRESSOR PROTEINS;

EID: 84872679699     PISSN: 09699961     EISSN: 1095953X     Source Type: Journal    
DOI: 10.1016/j.nbd.2012.10.014     Document Type: Article

References (124)

1. Abell F., Krams M., et al. The neuroanatomy of autism: a voxel-based whole brain analysis of structural scans. Neuroreport 1999, 10(8):1647-1651.
2. Allan A.M., Liang X., et al. The loss of methyl-CpG binding protein 1 leads to autism-like behavioral deficits. Hum. Mol. Genet. 2008, 17(13):2047-2057.
3. Allen G., Courchesne E. Differential effects of developmental cerebellar abnormality on cognitive and motor functions in the cerebellum: an fMRI study of autism. Am. J. Psychiatry 2003, 160(2):262-273.
4. Asano E., Chugani D.C., et al. Autism in tuberous sclerosis complex is related to both cortical and subcortical dysfunction. Neurology 2001, 57(7):1269-1277.
5. Association, A.P. Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR 2000, Amer Psychiatric Pub. Fourth edition.
6. Astrinidis A., Cash T.P., et al. Tuberin, the tuberous sclerosis complex 2 tumor suppressor gene product, regulates Rho activation, cell adhesion and migration. Oncogene 2002, 21(55):8470-8476.
7. Au K.S., Hebert A.A., et al. Complete inactivation of the TSC2 gene leads to formation of hamartomas. Am. J. Hum. Genet. 1999, 65(6):1790-1795.
8. Au K.S., Williams A.T., et al. Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. Genet. Med. 2007, 9(2):88-100.
9. Aylward E.H., Minshew N.J., et al. MRI volumes of amygdala and hippocampus in non-mentally retarded autistic adolescents and adults. Neurology 1999, 53(9):2145-2150.
10. Bailey A., Luthert P., et al. A clinicopathological study of autism. Brain 1998, 121(Pt 5):889-905.
11. Bailey D.B., Mesibov G.B., et al. Autistic behavior in young boys with fragile X syndrome. J. Autism Dev. Disord. 1998, 28(6):499-508.
12. Barski J.J., Dethleffsen K., et al. Cre recombinase expression in cerebellar Purkinje cells. Genesis 2000, 28(3-4):93-98.
13. Bertrand J., Mars A., et al. Prevalence of autism in a United States population: the Brick Township, New Jersey, investigation. Pediatrics 2001, 108(5):1155-1161.
14. Bhaskar P.T., Hay N. The two TORCs and Akt. Dev. Cell 2007, 12(4):487-502.
15. Binder J.R. Neuroanatomy of language processing studied with functional MRI. Clin. Neurosci. 1997, 4(2):87-94.
16. Binder J.R., Frost J.A., et al. Human brain language areas identified by functional magnetic resonance imaging. J. Neurosci. 1997, 17(1):353-362.
17. Boer K., Troost D., et al. Clinicopathological and immunohistochemical findings in an autopsy case of tuberous sclerosis complex. Neuropathology 2008, 28(6):577-590.
18. Brereton A.V., Tonge B.J., et al. Psychopathology in children and adolescents with autism compared to young people with intellectual disability. J. Autism Dev. Disord. 2006, 36(7):863-870.
19. Butler M.G., Dasouki M.J., et al. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J. Med. Genet. 2005, 42(4):318-321.
20. Caddy K.W., Biscoe T.J. Structural and quantitative studies on the normal C3H and Lurcher mutant mouse. Philos. Trans. R. Soc. Lond. B Biol. Sci. 1979, 287(1020):167-201.
21. Cappon D. Clinical manifestations of autism and schizophrenia in childhood. Can. Med. Assoc. J. 1953, 69(1):44-49.
22. Chan J.A., Zhang H., et al. Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. J. Neuropathol. Exp. Neurol. 2004, 63(12):1236-1242.
23. Cheon K.A., Kim Y.S., et al. Involvement of the anterior thalamic radiation in boys with high functioning autism spectrum disorders: a Diffusion Tensor Imaging study. Brain Res. 2011, 1417:77-86.
24. Chevere-Torres I., Maki J.M., et al. Impaired social interactions and motor learning skills in tuberous sclerosis complex model mice expressing a dominant/negative form of tuberin. Neurobiol. Dis. 2012, 45(1):156-164.
25. Coldren J.T., Halloran C. Spatial reversal as a measure of executive functioning in children with autism. J. Genet. Psychol. 2003, 164(1):29-41.
26. Consortium, E.C.T.S Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 1993, 75(7):1305-1315.
27. Corbett B.A., Constantine L.J., et al. Examining executive functioning in children with autism spectrum disorder, attention deficit hyperactivity disorder and typical development. Psychiatry Res. 2009, 166(2-3):210-222.
28. Courchesne E. Brainstem, cerebellar and limbic neuroanatomical abnormalities in autism. Curr. Opin. Neurobiol. 1997, 7(2):269-278.
29. Courchesne E., Pierce K. Brain overgrowth in autism during a critical time in development: implications for frontal pyramidal neuron and interneuron development and connectivity. Int. J. Dev. Neurosci. 2005, 23(2-3):153-170.
30. Courchesne E., Townsend J., et al. The brain in infantile autism: posterior fossa structures are abnormal. Neurology 1994, 44(2):214-223.
31. Crawley J.N. Mouse behavioral assays relevant to the symptoms of autism. Brain Pathol. 2007, 17(4):448-459.
32. Crawley J.N. Behavioral phenotyping strategies for mutant mice. Neuron 2008, 57(6):809-818.
33. Crino P.B., Nathanson K.L., et al. The tuberous sclerosis complex. N. Engl. J. Med. 2006, 355(13):1345-1356.
34. Crino P.B., Aronica E., et al. Biallelic TSC gene inactivation in tuberous sclerosis complex. Neurology 2010, 74(21):1716-1723.
35. Curatolo P., Napolioni V., et al. Autism spectrum disorders in tuberous sclerosis: pathogenetic pathways and implications for treatment. J. Child Neurol. 2012, 25(7):873-880.
36. Dabora S.L., Jozwiak S., et al. Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am. J. Hum. Genet. 2001, 68(1):64-80.
37. Dawson G., Meltzoff A.N., et al. Neuropsychological correlates of early symptoms of autism. Child Dev. 1998, 69(5):1276-1285.
38. de Vries P.J., Hunt A., et al. The psychopathologies of children and adolescents with tuberous sclerosis complex (TSC): a postal survey of UK families. Eur. Child Adolesc. Psychiatry 2007, 16(1):16-24.
39. DiMario F.J. Brain abnormalities in tuberous sclerosis complex. J. Child Neurol. 2004, 19(9):650-657.
40. Egawa J., Watanabe Y., et al. Reduced thalamus volume in non-right-handed male patients with autism spectrum disorders. Psychiatry Clin. Neurosci. 2011, 65(4):395.
41. Ehninger D., Silva A.J. Rapamycin for treating tuberous sclerosis and autism spectrum disorders. Trends Mol. Med. 2011, 17(2):78-87.
42. Ehninger D., Han S., et al. Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis. Nat. Med. 2008, 14(8):843-848.
43. Ehninger D., Sano Y., et al. Gestational immune activation and Tsc2 haploinsufficiency cooperate to disrupt fetal survival and may perturb social behavior in adult mice. Mol. Psychiatry 2012, 17(1):62-70.
44. Eluvathingal T.J., Behen M.E., et al. Cerebellar lesions in tuberous sclerosis complex: neurobehavioral and neuroimaging correlates. J. Child Neurol. 2006, 21(10):846-851.
45. Exner C., Weniger G., et al. Cerebellar lesions in the PICA but not SCA territory impair cognition. Neurology 2004, 63(11):2132-2135.
46. Fatemi S.H., Halt A.R., et al. Purkinje cell size is reduced in cerebellum of patients with autism. Cell. Mol. Neurobiol. 2002, 22(2):171-175.
47. Fatemi S.H., Aldinger K.A., et al. Consensus paper: pathological role of the cerebellum in autism. Cerebellum 2012, 11(3):777-807.
48. Fletcher P.C., Happe F., et al. Other minds in the brain: a functional imaging study of "theory of mind" in story comprehension. Cognition 1995, 57(2):109-128.
49. Folstein S., Rutter M. Infantile autism: a genetic study of 21 twin pairs. J. Child Psychol. Psychiatry 1977, 18(4):297-321.
50. Frith C.D., Frith U. Interacting minds-a biological basis. Science 1999, 286(5445):1692-1695.
51. Gangloff Y.G., Mueller M., et al. Disruption of the mouse mTOR gene leads to early postimplantation lethality and prohibits embryonic stem cell development. Mol. Cell. Biol. 2004, 24(21):9508-9516.
52. Gillberg I.C., Gillberg C., et al. Autistic behaviour and attention deficits in tuberous sclerosis: a population-based study. Dev. Med. Child Neurol. 1994, 36(1):50-56.
53. Gonzalo-Ruiz A., Leichnetz G.R. Connections of the caudal cerebellar interpositus complex in a new world monkey (Cebus apella). Brain Res. Bull. 1990, 25(6):919-927.
54. Goorden S.M., van Woerden G.M., et al. Cognitive deficits in Tsc1+/- mice in the absence of cerebral lesions and seizures. Ann. Neurol. 2007, 62(6):648-655.
55. Gordon N. The cerebellum and cognition. Eur. J. Paediatr. Neurol. 2007, 11(4):232-234.
56. Green A.J., Johnson P.H., et al. The tuberous sclerosis gene on chromosome 9q34 acts as a growth suppressor. Hum. Mol. Genet. 1994, 3(10):1833-1834.
57. Green A.J., Smith M., et al. Loss of heterozygosity on chromosome 16p13.3 in hamartomas from tuberous sclerosis patients. Nat. Genet. 1994, 6(2):193-196.
58. Guess D., Carr E. Emergence and maintenance of stereotypy and self-injury. Am. J. Ment. Retard. 1991, 96(3):299-319. (discussion 321-244).
59. Hashimoto T., Tayama M., et al. Development of the brainstem and cerebellum in autistic patients. J. Autism Dev. Disord. 1995, 25(1):1-18.
60. Henske E.P., Scheithauer B.W., et al. Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions. Am. J. Hum. Genet. 1996, 59(2):400-406.
61. Henske E.P., Wessner L.L., et al. Loss of tuberin in both subependymal giant cell astrocytomas and angiomyolipomas supports a two-hit model for the pathogenesis of tuberous sclerosis tumors. Am. J. Pathol. 1997, 151(6):1639-1647.
62. Hernandez O., Way S., et al. Generation of a conditional disruption of the Tsc2 gene. Genesis 2007, 45(2):101-106.
63. Hilber P., Lorivel T., et al. Stress and anxious-related behaviors in Lurcher mutant mice. Brain Res. 2004, 1003(1-2):108-112.
64. Hofvander B., Delorme R., et al. Psychiatric and psychosocial problems in adults with normal-intelligence autism spectrum disorders. BMC Psychiatry 2009, 9:35.
65. Hoke K.L., Ryan M.J., et al. Integration of sensory and motor processing underlying social behaviour in tungara frogs. Proc. Biol. Sci. 2007, 274(1610):641-649.
66. Huang J., Manning B.D. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem. J. 2008, 412(2):179-190.
67. Hunt A., Dennis J. Psychiatric disorder among children with tuberous sclerosis. Dev. Med. Child Neurol. 1987, 29(2):190-198.
68. Hunt A., Shepherd C. A prevalence study of autism in tuberous sclerosis. J. Autism Dev. Disord. 1993, 23(2):323-339.
69. Inoki K., Li Y., et al. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol. 2002, 4(9):648-657.
70. Inoki K., Li Y., et al. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 2003, 17(15):1829-1834.
71. Kaufmann W.E., Cooper K.L., et al. Specificity of cerebellar vermian abnormalities in autism: a quantitative magnetic resonance imaging study. J. Child Neurol. 2003, 18(7):463-470.
72. Kelly R.M., Strick P.L. Cerebellar loops with motor cortex and prefrontal cortex of a nonhuman primate. J. Neurosci. 2003, 23(23):8432-8444.
73. Kennedy D.P., Redcay E., et al. Failing to deactivate: resting functional abnormalities in autism. Proc. Natl. Acad. Sci. U. S. A. 2006, 103(21):8275-8280.
74. Krienen F.M., Buckner R.L. Segregated fronto-cerebellar circuits revealed by intrinsic functional connectivity. Cereb. Cortex 2009, 19(10):2485-2497.
75. Kwon C.H., Luikart B.W., et al. Pten regulates neuronal arborization and social interaction in mice. Neuron 2006, 50(3):377-388.
76. Lee T.L., Raygada M.J., et al. Integrative gene network analysis provides novel regulatory relationships, genetic contributions and susceptible targets in autism spectrum disorders. Gene 2012, 496(2):88-96.
77. Martin L.A., Goldowitz D., et al. Repetitive behavior and increased activity in mice with Purkinje cell loss: a model for understanding the role of cerebellar pathology in autism. Eur. J. Neurosci. 2012, 31(3):544-555.
78. Marui T., Hashimoto O., et al. Association between the neurofibromatosis-1 (NF1) locus and autism in the Japanese population. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004, 131B(1):43-47.
79. Matson J.L., Shoemaker M. Intellectual disability and its relationship to autism spectrum disorders. Res. Dev. Disabil. 2009, 30(6):1107-1114.
80. Meikle L., Talos D.M., et al. A mouse model of tuberous sclerosis: neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival. J. Neurosci. 2007, 27(21):5546-5558.
81. Middleton F.A., Strick P.L. Basal ganglia and cerebellar loops: motor and cognitive circuits. Brain Res. Brain Res. Rev. 2000, 31(2-3):236-250.
82. Middleton F.A., Strick P.L. Cerebellar projections to the prefrontal cortex of the primate. J. Neurosci. 2001, 21(2):700-712.
83. Moy S.S., Nadler J.J., et al. Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behavior in mice. Genes Brain Behav. 2004, 3(5):287-302.
84. Moy S.S., Nadler J.J., et al. Mouse behavioral tasks relevant to autism: phenotypes of 10 inbred strains. Behav. Brain Res. 2007, 176(1):4-20.
85. Muhle R., Trentacoste S.V., et al. The genetics of autism. Pediatrics 2004, 113(5):e472-e486.
86. Murakami M., Ichisaka T., et al. mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Mol. Cell. Biol. 2004, 24(15):6710-6718.
87. Nie D., Di Nardo A., et al. Tsc2-Rheb signaling regulates EphA-mediated axon guidance. Nat. Neurosci. 2010, 13(2):163-172.
88. Niida Y., Stemmer-Rachamimov A.O., et al. Survey of somatic mutations in tuberous sclerosis complex (TSC) hamartomas suggests different genetic mechanisms for pathogenesis of TSC lesions. Am. J. Hum. Genet. 2001, 69(3):493-503.
89. Numis A.L., Major P., et al. Identification of risk factors for autism spectrum disorders in tuberous sclerosis complex. Neurology 2011, 76(11):981-987.
90. Osborne J.P., Fryer A., et al. Epidemiology of tuberous sclerosis. Ann. N. Y. Acad. Sci. 1991, 615:125-127.
91. Palmen S.J., van Engeland H., et al. Neuropathological findings in autism. Brain 2004, 127(Pt 12):2572-2583.
92. Paulus K.S., Magnano I., et al. Pure post-stroke cerebellar cognitive affective syndrome: a case report. Neurol. Sci. 2004, 25(4):220-224.
93. Peca J., Feliciano C., et al. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 2011, 472(7344):437-442.
94. Prevention, C.f.D.C.a. Prevalence of Autism Spectrum Disorders-Autism and Developmental Disabilities Monitoring Network, United States, 2006. Atlanta, Centers for Disease Control and Prevention 2006, 58:1-20.
95. Qin W., Chan J.A., et al. Analysis of TSC cortical tubers by deep sequencing of TSC1, TSC2 and KRAS demonstrates that small second-hit mutations in these genes are rare events. Brain Pathol. 2010, 20(6):1096-1105.
96. Reith R.M., Way S., et al. Loss of the tuberous sclerosis complex protein tuberin causes Purkinje cell degeneration. Neurobiol. Dis. 2011, 43(1):113-122.
97. Rogers T.D., Dickson P.E., et al. Connecting the dots of the cerebro-cerebellar role in cognitive function: neuronal pathways for cerebellar modulation of dopamine release in the prefrontal cortex. Synapse 2011, 65(11):1204-1212.
98. Rutter M. Diagnosis and definition of childhood autism. J. Autism Child. Schizophr. 1978, 8(2):139-161.
99. Saab C.Y., Willis W.D. The cerebellum: organization, functions and its role in nociception. Brain Res. Brain Res. Rev. 2003, 42(1):85-95.
100. Sarbassov D.D., Ali S.M., et al. Growing roles for the mTOR pathway. Curr. Opin. Cell Biol. 2005, 17(6):596-603.
101. Schmahmann J.D., Sherman J.C. The cerebellar cognitive affective syndrome. Brain 1998, 121(Pt 4):561-579.
102. Skokauskas N., Gallagher L. Mental health aspects of autistic spectrum disorders in children. J. Intellect. Disabil. Res. 2012, 56(3):248-257.
103. Smalley S.L., Tanguay P.E., et al. Autism and tuberous sclerosis. J. Autism Dev. Disord. 1992, 22(3):339-355.
104. Tamura R., Kitamura H., et al. Reduced thalamic volume observed across different subgroups of autism spectrum disorders. Psychiatry Res. 2010, 184(3):186-188.
105. Tavano A., Grasso R., et al. Disorders of cognitive and affective development in cerebellar malformations. Brain 2007, 130(Pt 10):2646-2660.
106. Tavazoie S.F., Alvarez V.A., et al. Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nat. Neurosci. 2005, 8(12):1727-1734.
107. Thomas A., Burant A., et al. Marble burying reflects a repetitive and perseverative behavior more than novelty-induced anxiety. Psychopharmacology (Berl) 2009, 204(2):361-373.
108. Tsai P.T., Hull C., et al. Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature 2012, 488(7413):647-651.
109. Tsatsanis K.D., Rourke B.P., et al. Reduced thalamic volume in high-functioning individuals with autism. Biol. Psychiatry 2003, 53(2):121-129.
110. van Slegtenhorst M., de Hoogt R., et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 1997, 277(5327):805-808.
111. Vargas D.L., Nascimbene C., et al. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann. Neurol. 2005, 57(1):67-81.
112. Waltereit R., Japs B., et al. Epilepsy and Tsc2 haploinsufficiency lead to autistic-like social deficit behaviors in rats. Behav. Genet. 2011, 41(3):364-372.
113. Way S.W., McKenna J., et al. Loss of Tsc2 in radial glia models the brain pathology of tuberous sclerosis complex in the mouse. Hum. Mol. Genet. 2009, 18(7):1252-1265.
114. Weber A.M., Egelhoff J.C., et al. Autism and the cerebellum: evidence from tuberous sclerosis. J. Autism Dev. Disord. 2000, 30(6):511-517.
115. Wing L. Language, social, and cognitive impairments in autism and severe mental retardation. J. Autism Dev. Disord. 1981, 11(1):31-44.
116. Wiznitzer M. Autism and tuberous sclerosis. J. Child Neurol. 2004, 19(9):675-679.
117. Wolpert D.M., Doya K., et al. A unifying computational framework for motor control and social interaction. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2003, 358(1431):593-602.
118. Wong V. Study of the relationship between tuberous sclerosis complex and autistic disorder. J. Child Neurol. 2006, 21(3):199-204.
119. Yamamoto T., Yoshida K., et al. The medial dorsal nucleus is one of the thalamic relays of the cerebellocerebral responses to the frontal association cortex in the monkey: horseradish peroxidase and fluorescent dye double staining study. Brain Res. 1992, 579(2):315-320.
120. Yip J., Soghomonian J.J., et al. Decreased GAD65 mRNA levels in select subpopulations of neurons in the cerebellar dentate nuclei in autism: an in situ hybridization study. Autism Res. 2009, 2(1):50-59.
121. Young D.M., Schenk A.K., et al. Altered ultrasonic vocalizations in a tuberous sclerosis mouse model of autism. Proc. Natl. Acad. Sci. U. S. A. 2010, 107(24):11074-11079.
122. Zhang Y., Gao X., et al. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat. Cell Biol. 2003, 5(6):578-581.
123. Zhou J., Shrikhande G., et al. Tsc1 mutant neural stem/progenitor cells exhibit migration deficits and give rise to subependymal lesions in the lateral ventricle. Genes Dev. 2011, 25(15):1595-1600.
124. Zuo J., De Jager P.L., et al. Neurodegeneration in Lurcher mice caused by mutation in delta2 glutamate receptor gene. Nature 1997, 388(6644):769-773.