局灶性皮質發育不良與兒童孤獨癥譜系障礙的相關性研究進展_Journal of Epilepsy

Authors：

胡俊杰 ¹ ,  廖建湘 ²

1. ;
2. ;

Corresponding?author：

廖建湘, Email: liaojianxiang@vip.sina.com

Keywords：

結節性硬化癥; 局灶性皮質發育不良; 兒童孤獨癥譜系障礙; 癲癇發病機制

DOI：

10.7507/2096-0247.20200022

Video：

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Abstract Full text Figures/Tables Video References Cited by

結節性硬化癥（Tuberous sclerosis complex，TSC）是一種常染色體顯性遺傳疾病，已被證實與兒童局灶性腦皮質發育（Focal cortical dysplasia，FCD）和孤獨癥譜系障礙（Autism spectrum disorder，ASD）的發病機理有關。作為研究 FCD 以及 ASD 的模型，許多文獻中都提到了 TSC，但目前尚不清楚具體機制。文章對 TSC 與 FCD 和 TSC與 ASD 患兒之間的關系，以及FCD與 ASD 之間的聯系，提出新的想法。

Citation： 胡俊杰, 廖建湘. 局灶性皮質發育不良與兒童孤獨癥譜系障礙的相關性研究進展. Journal of Epilepsy, 2020, 6(2): 127-132. doi: 10.7507/2096-0247.20200022 Copy

1.	Peter E Davis, Jurriaan M Peters1, Darcy A Krueger, et al. Tuberous sclerosis: a new frontier in targeted treatment of autism. Neurotherapeutics, 2015, 12(3): 572-583.
2.	Lipton JO, Sahin M. The neurology ofmTOR. Neuron, 2014, 84(2): 275-291.
3.	Feliciano DM, Lin TV, Hartman NW, et al. A circuitry and biochemical basis for tuberous sclerosis symptoms: from epilepsy to neurocognitive deficits. Int J Dev Neurosci, 2013, 31(7): 667-678.
4.	Chen J, Alberts I, Li X. Dysregulation of the IGF-I/PI3K/AKT/ mTOR signaling pathway in autism spectrum disorders. Int J Dev Neurosci, 2014, 35(1): 35-41.
5.	Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell, 2012, 149(2): 274-293.
6.	Tang G, Gudsnuk K, Kuo SH, et al. Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron, 2014, 83(5): 1131-1143.
7.	Di Nardo A, Wertz MH, Kwiatkowski E, et al. Neuronal Tsc1/2 complex controls autophagy through AMPK-dependent regulation of ULK1. Hum Mol Genet, 2014, 23(14): 3865-3874.
8.	Di Nardo A, Kramvis I, Cho N, et al. Tuberous sclerosis complex activity is required to control neuronal stress responses in an mTOR-dependent manner. J Neurosci, 2009, 29(18): 5926-5937.
9.	Lim K-C, Crino PB. Focal malformations ofcortical development: new vistas for molecular pathogenesis. Neuroscience, 2013, 252(1): 262-276.
10.	Lena H. Nguyen, Travorn Mahadeo, Angelique Bordey. mTOR hyperactivity levels influence the severity of epilepsy and associated neuropathology in an experimental model of tuberous sclerosis complex and focal cortical dysplasia, The Journal of Neuroscience, 2019, 39(14): 2762-2773.
11.	Michael Wong. Mammalian target of rapamycin (mTOR) activation in focal cortical dysplasia and related focal cortical malformations. Exp Neurol, 2013, 244(1): 22-26.
12.	Palmini A, Najm I, Avanzini G, et al. Terminology and classification of cortical dysplasias. Neurology, 2004, 62(Suppl 3): S2-S8.
13.	Blumcke I, Thom M, Aronica E, et al. The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia, 2011, 52(1): 158-174.
14.	Barkovich AJ, Kuzniecky RI, Jackson GD, et al. A developmental and genetic classification for malformations of cortical development. Neurology, 2005, 65(12): 1873-1887.
15.	Yasin SA, Latak K, Becherini F, et al. Balloon cells in human cortical dysplasia and tuberous sclerosis: isolation of a pathological progenitor-like cell. Acta Neuropathol, 2010, 120(1): 85-96.
16.	Boer K, Lucassen PJ, Spliet WG, et al. Doublecortin-like (DCL) expression in focal cortical dysplasia and cortical tubers. Epilepsia, 2009, 50(12): 2629-2637.
17.	Fauser S, Becker A, Schulze-Bonhage A, et al. CD34-immunoreactive balloon cells in cortical malformations. Acta Neuropathol, 2004, 108(4): 272-278.
18.	Lamparello P, Baybis M, Pollard J, et al. Developmental lineage of cell types in cortical dysplasia with balloon cells. Brain, 2007, 130(Pt 9): 2267-2276.
19.	Lee A, Maldanado M, Baybis M, et al. Markers of cellular proliferation are expressed in cortical tubers. Ann Neurol, 2003, 53(5): 668-673.
20.	Mizuguchi M, Yamanouchi Hl, Becker LE, et al. Doublecortin immunoreactivity in giant cells of tuberous sclerosis and focal cortical dysplasia. Acta Neuropathol, 2002, 104(4): 418-424.
21.	Becker AJ, Urbach H, Scheffler BJ, et al. Focal cortical dysplasia of Taylor’s balloon cell type: mutational analysis of the TSC1 gene indicates a pathogenic relationship to Tuberous Sclerosis. Ann Neurol, 2002, 52(1): 29-37.
22.	Schonberger A, Niehusmann P, Urbach H, et al. Increased frequency of distinct TSC2 alleleic variants in focal cortical dysplasias with balloon cells and mineralization. Neuropathol, 2009, 29(5): 559-565.
23.	Gumbinger C, Rohsbach CB, Schulze-Bonhage A, et al. Focal cortical dysplasia: a genotype-phenotype analysis of polymorphisms and mutations in the TSC genes. Epilepsia, 2009, 50(6): 1396-1408.
24.	Grajkowski W, Kotulska K, Matyja E, et al. Expression of tuberin and hamartin in tuberous sclerosis complex-associated and sporadic cortical dysplasia of Taylor’s balloon cell type. Folia Neuropathol, 2008, 46(1): 43-48.
25.	Lugnier C, Majores M, Fassunke J, et al. Hamartin variants that are frequent in focal dysplasias and cortical tubers have reduced tuberin binding and aberrant subcellular distribution in vitro. J Neuropathol Exp Neurol, 2009, 68(10): 1136-1146.
26.	Baybis M, Yu J, Lee A, et al. mTOR cascade activation distinguishes tubers from focal cortical dysplasia. Ann. Neurol, 2004, 56(4): 478-487.
27.	Ljungberg MC, Bhattacharjee MB, Lu Y, et al. Activation of mammalian target of rapamycin in cytomegalic neurons of human cortical dysplasia. Ann Neurol, 2006, 60(4): 420-429.
28.	Miyata H, Chiang ACY, Vinters HV. Insulin signaling pathways in cortical dysplasia and TSC-tubers: tissue microarray analysis. Ann Neurol, 2004, 56(4): 510-519.
29.	Schick V, Majores M, Engels G, et al. Differential Pi3K-pathway activation in cortical tubers and focal cortical dysplasias with balloon cells. Brain Pathol, 2007, 17(2): 165-173.
30.	Ljungberg MC, Sunnen CN, Lugo JN, et al. D’Arcangelo G. Rapamycin suppresses seizures and neuronal hypertrophy in a mouse model of cortical dysplasia. Dis Model Mech, 2009, 2(7-8): 389-398.
31.	Kwon CH, Zhu X, Zhang J, et al. mTOR is required for hypertrophy of Pten-deficient neuronal soma in vivo. Proc Natl Acad Sci USA, 2003, 100(22): 12923-12928.
32.	Zhou J, Blundell J, Ogawa S, et al. Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neuralspecific Pten knock-out mice. J Neurosci, 2009, 29(6): 1773-1783.
33.	李國瑞, 余圣陶. 自閉癥診斷與治療研究動向綜述. 心理科學, 2004, 27(6): 1449-1450.
34.	Romina Moavero, Arianna Benvenuto, Leonardo Emberti Gialloreti, et al. Early clinical predictors of autism spectrum disorder in infants with tuberous sclerosis complex: Results from the EPISTOP study. J Clin Med, 2019, 8(6): 788.
35.	Kelleher RJ, Bear MF. The autistic neuron: troubled translation? Cell, 2008, 13(3): 401-406.
36.	Auerbach BD, Osterweil EK, Bear MF. Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature, 2011, 480(7375): 63-68.
37.	Won H, Mah W, Kim E. Autism spectrum disorder causes, mechanisms, and treatments: focus on neuronal synapses. Front Mol Neurosci, 2013, 6(1): 19.
38.	Anna K, Prohl, Benoit Scherrer, Xavier Tomas-Fernandez, et al. Early white matter development is abnormal in tuberous sclerosis complex patients who develop autism spectrum disorder. Journal of Neurodevelopmental Disorders, 2019, 11(1): 36.
39.	Travers BGB, Adluru N, Ennis C, et al. Diffusion tensor imaging in autism spectrum disorder: a review. Autism Res, 2012, 5(5): 289-313.
40.	Rane P, Cochran D, Hodge SM, et al. Connectivity in autism: a review of MRI connectivity studies. Harv Rev Psychiatry, 2015, 23(4): 223-244.
41.	Peters JM, Sahin M, Vogel-Farley VK, et al. Loss of white matter microstructural integrity is associated with adverse neurological outcome in tuberous sclerosis complex. Acad Radiol, 2012, 19(1): 17-25.
42.	Baumer FM, Peters JM, Clancy S, Prohl AK, Prabhu SP, et al. Corpus callosum white matter diffusivity reflects cumulative neurological comorbidity in tuberous sclerosis complex. Cereb Cortex, 2017, (Md): 1-8.
43.	Lewis WW, Sahin M, Scherrer B, et al. Impaired language pathways in tuberous sclerosis complex patients with autism spectrum disorders. Cereb Cortex, 2013, 23(7): 1526-32.
44.	Chevere-Torres I, Kaphzan H, Bhattacharya A, et al. Metabotropic glutamate receptor-dependent long-term depression is impaired due to elevated ERK signaling in the DeltaRG mouse model of tuberous sclerosis complex. Neurobiol Dis, 2012, 45(3): 1101-1110.
45.	H ou, L, Klann E. Activation of the phosphoinositide 3-kinaseAkt-mammalian target ofrapamycin signaling pathway is required for metabotropic glutamate receptor-dependent long-term depression. J Neurosci, 2004, 24(28): 6352-6361.
46.	Tavazoie SF, Alvarez VA, Ridenour DA, et al. Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nat Neurosci, 2005, 8(12): 1727-1734.
47.	Santini E, Klann E. Reciprocal signaling between translational control pathways and synaptic proteins in autism spectrum disorders. Sci Signal, 2014, 7(349): 10.
48.	Tsai PT, Hull C, Chu Y, et al. Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature, 2012, 488(7413): 647-651.
49.	Zeng L-H, Ouyang Y, Gazit V, et al. Abnormal glutamate homeostasis and impaired synaptic plasticity and learning in a mouse model of tuberous sclerosis complex. Neurobiol Dis, 2007, 28(2): 184-196.
50.	Bateup HS, Johnson CA, Denefrio CL, et al. Excitatory/ inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis. Neuron, 2013, 78(3): 510-522.
51.	Curatolo P. Mechanistic target of rapamycin (mTOR) in tuberous sclerosis complex-associated epilepsy. Pediatr Neurol, 2014, 52(3): 281-289.
52.	Crino PB. Evolving neurobiology of tuberous sclerosis complex. Acta Neuropathol, 2013, 125(3): 317-332.
53.	Bolton P, Park RJ, Higgins J, et al. Neuroepileptic determinants of autism spectrum disorders in tuberous sclerosis complex. Brain, 2002, 125(Pt 6): 1247-1255.
54.	Weber AM, Egelhoff JC, McKellop JM, et al. Autism and the cerebellum: evidence from tuberous sclerosis. J Autism Dev Disord, 2000, 30(6): 511-517.
55.	Meikle L, Talos DM, Onda H, 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.
56.	Eluvathingal TJ, Behen ME, Chugani HT, et al. Cerebellar lesions in tuberous sclerosis complex: neurobehavioral and neuroimaging correlates. J Child Neurol, 2006, 21(10): 846-851.
57.	Geschwind DH, Levitt P. Autism spectrum disorders: developmental disconnection syndromes. Curr Opin Neurobiol, 2007, 17(1): 103-111.
58.	Wass S. Distortions and disconnections: disrupted brain connectivity in autism. Brain Cogn, 2011, 75(1): 18-28.
59.	Peters JM, Taquet M, Prohl AK, et al. Diffusion tensor imaging and related techniques in tuberous sclerosis complex: review and future directions. Future Neurol, 2013, 8(5): 583-597.
60.	Jeste SS, Sahin M, Bolton P, et al. Characterization of autism in young children with tuberous sclerosis complex. J Child Neurol, 2008, 23(5): 520-525.
61.	Curatolo P, Maria BL. Tuberous sclerosis. Handb Clin Neurol, 2013, 111(1): 323-331.
62.	Spurling Jeste S, Wu JY, Senturk D, et al. Early development altrajectories associated with ASD in infants with tuberous sclerosiscomplex. Neurology, 2014, 83(2): 160-168.
63.	Careaga M, Van de Water J, Ashwood P. Immune dysfunction inautism: a pathway to treatment. Neurotherapeutics, 2010, 7(1): 283-292.
64.	Reith RM, McKenna J, Wu H, et al. Loss of Tsc2 in Purkinje cells is associated with autistic-like behavior in a mouse model of tuberous sclerosis complex. Neurobiol Dis, 2013, 51(1): 93-103.
65.	Talos DM, Sun H, Zhou X, et al. The interaction between early life epilepsy and autistic-like behavioral consequences: a role for the mammalian target of rapamycin (mTOR) pathway. PLoS ONE, 2012, 7(5): e35885.
66.	McMahon JJ, Yu W, Yang J, et al. Seizure-dependent mTOR activation in 5-HT neurons promotes autism-like behaviors in mice. Neurobiol Dis, 2015, 73(2): 296-306.
67.	Casanova MF, et al. Focal cortical dysplasias in autism spectrum disorders. Acta Neuropathol Commun, 2013, 11(1): 67.

1. Peter E Davis, Jurriaan M Peters1, Darcy A Krueger, et al. Tuberous sclerosis: a new frontier in targeted treatment of autism. Neurotherapeutics, 2015, 12(3): 572-583.
2. Lipton JO, Sahin M. The neurology ofmTOR. Neuron, 2014, 84(2): 275-291.
3. Feliciano DM, Lin TV, Hartman NW, et al. A circuitry and biochemical basis for tuberous sclerosis symptoms: from epilepsy to neurocognitive deficits. Int J Dev Neurosci, 2013, 31(7): 667-678.
4. Chen J, Alberts I, Li X. Dysregulation of the IGF-I/PI3K/AKT/ mTOR signaling pathway in autism spectrum disorders. Int J Dev Neurosci, 2014, 35(1): 35-41.
5. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell, 2012, 149(2): 274-293.
6. Tang G, Gudsnuk K, Kuo SH, et al. Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron, 2014, 83(5): 1131-1143.
7. Di Nardo A, Wertz MH, Kwiatkowski E, et al. Neuronal Tsc1/2 complex controls autophagy through AMPK-dependent regulation of ULK1. Hum Mol Genet, 2014, 23(14): 3865-3874.
8. Di Nardo A, Kramvis I, Cho N, et al. Tuberous sclerosis complex activity is required to control neuronal stress responses in an mTOR-dependent manner. J Neurosci, 2009, 29(18): 5926-5937.
9. Lim K-C, Crino PB. Focal malformations ofcortical development: new vistas for molecular pathogenesis. Neuroscience, 2013, 252(1): 262-276.
10. Lena H. Nguyen, Travorn Mahadeo, Angelique Bordey. mTOR hyperactivity levels influence the severity of epilepsy and associated neuropathology in an experimental model of tuberous sclerosis complex and focal cortical dysplasia, The Journal of Neuroscience, 2019, 39(14): 2762-2773.
11. Michael Wong. Mammalian target of rapamycin (mTOR) activation in focal cortical dysplasia and related focal cortical malformations. Exp Neurol, 2013, 244(1): 22-26.
12. Palmini A, Najm I, Avanzini G, et al. Terminology and classification of cortical dysplasias. Neurology, 2004, 62(Suppl 3): S2-S8.
13. Blumcke I, Thom M, Aronica E, et al. The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia, 2011, 52(1): 158-174.
14. Barkovich AJ, Kuzniecky RI, Jackson GD, et al. A developmental and genetic classification for malformations of cortical development. Neurology, 2005, 65(12): 1873-1887.
15. Yasin SA, Latak K, Becherini F, et al. Balloon cells in human cortical dysplasia and tuberous sclerosis: isolation of a pathological progenitor-like cell. Acta Neuropathol, 2010, 120(1): 85-96.
16. Boer K, Lucassen PJ, Spliet WG, et al. Doublecortin-like (DCL) expression in focal cortical dysplasia and cortical tubers. Epilepsia, 2009, 50(12): 2629-2637.
17. Fauser S, Becker A, Schulze-Bonhage A, et al. CD34-immunoreactive balloon cells in cortical malformations. Acta Neuropathol, 2004, 108(4): 272-278.
18. Lamparello P, Baybis M, Pollard J, et al. Developmental lineage of cell types in cortical dysplasia with balloon cells. Brain, 2007, 130(Pt 9): 2267-2276.
19. Lee A, Maldanado M, Baybis M, et al. Markers of cellular proliferation are expressed in cortical tubers. Ann Neurol, 2003, 53(5): 668-673.
20. Mizuguchi M, Yamanouchi Hl, Becker LE, et al. Doublecortin immunoreactivity in giant cells of tuberous sclerosis and focal cortical dysplasia. Acta Neuropathol, 2002, 104(4): 418-424.
21. Becker AJ, Urbach H, Scheffler BJ, et al. Focal cortical dysplasia of Taylor’s balloon cell type: mutational analysis of the TSC1 gene indicates a pathogenic relationship to Tuberous Sclerosis. Ann Neurol, 2002, 52(1): 29-37.
22. Schonberger A, Niehusmann P, Urbach H, et al. Increased frequency of distinct TSC2 alleleic variants in focal cortical dysplasias with balloon cells and mineralization. Neuropathol, 2009, 29(5): 559-565.
23. Gumbinger C, Rohsbach CB, Schulze-Bonhage A, et al. Focal cortical dysplasia: a genotype-phenotype analysis of polymorphisms and mutations in the TSC genes. Epilepsia, 2009, 50(6): 1396-1408.
24. Grajkowski W, Kotulska K, Matyja E, et al. Expression of tuberin and hamartin in tuberous sclerosis complex-associated and sporadic cortical dysplasia of Taylor’s balloon cell type. Folia Neuropathol, 2008, 46(1): 43-48.
25. Lugnier C, Majores M, Fassunke J, et al. Hamartin variants that are frequent in focal dysplasias and cortical tubers have reduced tuberin binding and aberrant subcellular distribution in vitro. J Neuropathol Exp Neurol, 2009, 68(10): 1136-1146.
26. Baybis M, Yu J, Lee A, et al. mTOR cascade activation distinguishes tubers from focal cortical dysplasia. Ann. Neurol, 2004, 56(4): 478-487.
27. Ljungberg MC, Bhattacharjee MB, Lu Y, et al. Activation of mammalian target of rapamycin in cytomegalic neurons of human cortical dysplasia. Ann Neurol, 2006, 60(4): 420-429.
28. Miyata H, Chiang ACY, Vinters HV. Insulin signaling pathways in cortical dysplasia and TSC-tubers: tissue microarray analysis. Ann Neurol, 2004, 56(4): 510-519.
29. Schick V, Majores M, Engels G, et al. Differential Pi3K-pathway activation in cortical tubers and focal cortical dysplasias with balloon cells. Brain Pathol, 2007, 17(2): 165-173.
30. Ljungberg MC, Sunnen CN, Lugo JN, et al. D’Arcangelo G. Rapamycin suppresses seizures and neuronal hypertrophy in a mouse model of cortical dysplasia. Dis Model Mech, 2009, 2(7-8): 389-398.
31. Kwon CH, Zhu X, Zhang J, et al. mTOR is required for hypertrophy of Pten-deficient neuronal soma in vivo. Proc Natl Acad Sci USA, 2003, 100(22): 12923-12928.
32. Zhou J, Blundell J, Ogawa S, et al. Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neuralspecific Pten knock-out mice. J Neurosci, 2009, 29(6): 1773-1783.
33. 李國瑞, 余圣陶. 自閉癥診斷與治療研究動向綜述. 心理科學, 2004, 27(6): 1449-1450.
34. Romina Moavero, Arianna Benvenuto, Leonardo Emberti Gialloreti, et al. Early clinical predictors of autism spectrum disorder in infants with tuberous sclerosis complex: Results from the EPISTOP study. J Clin Med, 2019, 8(6): 788.
35. Kelleher RJ, Bear MF. The autistic neuron: troubled translation? Cell, 2008, 13(3): 401-406.
36. Auerbach BD, Osterweil EK, Bear MF. Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature, 2011, 480(7375): 63-68.
37. Won H, Mah W, Kim E. Autism spectrum disorder causes, mechanisms, and treatments: focus on neuronal synapses. Front Mol Neurosci, 2013, 6(1): 19.
38. Anna K, Prohl, Benoit Scherrer, Xavier Tomas-Fernandez, et al. Early white matter development is abnormal in tuberous sclerosis complex patients who develop autism spectrum disorder. Journal of Neurodevelopmental Disorders, 2019, 11(1): 36.
39. Travers BGB, Adluru N, Ennis C, et al. Diffusion tensor imaging in autism spectrum disorder: a review. Autism Res, 2012, 5(5): 289-313.
40. Rane P, Cochran D, Hodge SM, et al. Connectivity in autism: a review of MRI connectivity studies. Harv Rev Psychiatry, 2015, 23(4): 223-244.
41. Peters JM, Sahin M, Vogel-Farley VK, et al. Loss of white matter microstructural integrity is associated with adverse neurological outcome in tuberous sclerosis complex. Acad Radiol, 2012, 19(1): 17-25.
42. Baumer FM, Peters JM, Clancy S, Prohl AK, Prabhu SP, et al. Corpus callosum white matter diffusivity reflects cumulative neurological comorbidity in tuberous sclerosis complex. Cereb Cortex, 2017, (Md): 1-8.
43. Lewis WW, Sahin M, Scherrer B, et al. Impaired language pathways in tuberous sclerosis complex patients with autism spectrum disorders. Cereb Cortex, 2013, 23(7): 1526-32.
44. Chevere-Torres I, Kaphzan H, Bhattacharya A, et al. Metabotropic glutamate receptor-dependent long-term depression is impaired due to elevated ERK signaling in the DeltaRG mouse model of tuberous sclerosis complex. Neurobiol Dis, 2012, 45(3): 1101-1110.
45. H ou, L, Klann E. Activation of the phosphoinositide 3-kinaseAkt-mammalian target ofrapamycin signaling pathway is required for metabotropic glutamate receptor-dependent long-term depression. J Neurosci, 2004, 24(28): 6352-6361.
46. Tavazoie SF, Alvarez VA, Ridenour DA, et al. Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nat Neurosci, 2005, 8(12): 1727-1734.
47. Santini E, Klann E. Reciprocal signaling between translational control pathways and synaptic proteins in autism spectrum disorders. Sci Signal, 2014, 7(349): 10.
48. Tsai PT, Hull C, Chu Y, et al. Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature, 2012, 488(7413): 647-651.
49. Zeng L-H, Ouyang Y, Gazit V, et al. Abnormal glutamate homeostasis and impaired synaptic plasticity and learning in a mouse model of tuberous sclerosis complex. Neurobiol Dis, 2007, 28(2): 184-196.
50. Bateup HS, Johnson CA, Denefrio CL, et al. Excitatory/ inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis. Neuron, 2013, 78(3): 510-522.
51. Curatolo P. Mechanistic target of rapamycin (mTOR) in tuberous sclerosis complex-associated epilepsy. Pediatr Neurol, 2014, 52(3): 281-289.
52. Crino PB. Evolving neurobiology of tuberous sclerosis complex. Acta Neuropathol, 2013, 125(3): 317-332.
53. Bolton P, Park RJ, Higgins J, et al. Neuroepileptic determinants of autism spectrum disorders in tuberous sclerosis complex. Brain, 2002, 125(Pt 6): 1247-1255.
54. Weber AM, Egelhoff JC, McKellop JM, et al. Autism and the cerebellum: evidence from tuberous sclerosis. J Autism Dev Disord, 2000, 30(6): 511-517.
55. Meikle L, Talos DM, Onda H, 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.
56. Eluvathingal TJ, Behen ME, Chugani HT, et al. Cerebellar lesions in tuberous sclerosis complex: neurobehavioral and neuroimaging correlates. J Child Neurol, 2006, 21(10): 846-851.
57. Geschwind DH, Levitt P. Autism spectrum disorders: developmental disconnection syndromes. Curr Opin Neurobiol, 2007, 17(1): 103-111.
58. Wass S. Distortions and disconnections: disrupted brain connectivity in autism. Brain Cogn, 2011, 75(1): 18-28.
59. Peters JM, Taquet M, Prohl AK, et al. Diffusion tensor imaging and related techniques in tuberous sclerosis complex: review and future directions. Future Neurol, 2013, 8(5): 583-597.
60. Jeste SS, Sahin M, Bolton P, et al. Characterization of autism in young children with tuberous sclerosis complex. J Child Neurol, 2008, 23(5): 520-525.
61. Curatolo P, Maria BL. Tuberous sclerosis. Handb Clin Neurol, 2013, 111(1): 323-331.
62. Spurling Jeste S, Wu JY, Senturk D, et al. Early development altrajectories associated with ASD in infants with tuberous sclerosiscomplex. Neurology, 2014, 83(2): 160-168.
63. Careaga M, Van de Water J, Ashwood P. Immune dysfunction inautism: a pathway to treatment. Neurotherapeutics, 2010, 7(1): 283-292.
64. Reith RM, McKenna J, Wu H, et al. Loss of Tsc2 in Purkinje cells is associated with autistic-like behavior in a mouse model of tuberous sclerosis complex. Neurobiol Dis, 2013, 51(1): 93-103.
65. Talos DM, Sun H, Zhou X, et al. The interaction between early life epilepsy and autistic-like behavioral consequences: a role for the mammalian target of rapamycin (mTOR) pathway. PLoS ONE, 2012, 7(5): e35885.
66. McMahon JJ, Yu W, Yang J, et al. Seizure-dependent mTOR activation in 5-HT neurons promotes autism-like behaviors in mice. Neurobiol Dis, 2015, 73(2): 296-306.
67. Casanova MF, et al. Focal cortical dysplasias in autism spectrum disorders. Acta Neuropathol Commun, 2013, 11(1): 67.

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