title: A circuitry and biochemical basis for tuberous sclerosis symptoms: from epilepsy to neurocognitive deficits.
abstract: Tuberous sclerosis complex (TSC) is an autosomal dominant monogenetic disorder that is characterized by the formation of benign tumors in several organs as well as brain malformations and neuronal defects. TSC is caused by inactivating mutations in one of two genes, TSC1 and TSC2, resulting in increased activity of the mammalian Target of Rapamycin (mTOR). Here, we explore the cytoarchitectural and functional CNS aberrations that may account for the neurological presentations of TSC, notably seizures, hydrocephalus, and cognitive and psychological impairments. In particular, recent mouse models of brain lesions are presented with an emphasis on using electroporation to allow the generation of discrete lesions resulting from loss of heterozygosity during perinatal development. Cortical lesions are thought to contribute to epileptogenesis and worsening of cognitive defects. However, it has recently been suggested that being born with a mutant allele without loss of heterozygosity and associated cortical lesions is sufficient to generate cognitive and neuropsychiatric problems. We will thus discuss the function of mTOR hyperactivity on neuronal circuit formation and the potential consequences of being born heterozygous on neuronal function and the biochemistry of synaptic plasticity, the cellular substrate of learning and memory. Ultimately, a major goal of TSC research is to identify the cellular and molecular mechanisms downstream of mTOR underlying the neurological manifestations observed in TSC patients and identify novel therapeutic targets to prevent the formation of brain lesions and restore neuronal function.
authors.affiliation: Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Feliciano
authors.forename: Tiffany V
authors.initials: TV
authors.lastname: Lin
authors.forename: Nathaniel W
authors.initials: NW
authors.lastname: Hartman
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Bartley
authors.forename: Cathryn
authors.initials: C
authors.lastname: Kubera
authors.forename: Lawrence
authors.initials: L
authors.lastname: Hsieh
authors.forename: Carlos
authors.initials: C
authors.lastname: Lafourcade
authors.forename: Rachel A
authors.initials: RA
authors.lastname: O'Keefe
authors.forename: Angelique
authors.initials: A
authors.lastname: Bordey
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology; D003072:Cognition Disorders / Q000209:etiology* / Q000235:genetics; D004195:Disease Models, Animal; D004827:Epilepsy / Q000209:etiology* / Q000235:genetics; D006801:Humans; D051379:Mice; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014402:Tuberous Sclerosis / Q000150:complications / Q000235:genetics / Q000473:pathology
chemical_list: C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: 4E-BP1; Autism; CNS; CSF; CreERT2; Dendrite; Differentiation; E; EEG; Epilepsy; FCDs; FMR1; FMRP; FMRP gene; FXS; GAP; GFAP; GTPase activating protein; IUE; LOH; LTD; LTP; LV; MRI; Mental retardation; Migration; Neurogenesis; P; PP2A; Progenitor cell; RGCs; Ras homolog enriched in brain; Rheb; S6K1; SEGA; SEN; SEZ; Seizures; Spine; Stem cell; SynI-Cre; Synapsin I promoter-driven Cre; TSC; TSC gene 1 or gene 2; TSC1 or TSC2; Tsc1(fl/fl); Tsc1(fl/mut); Tsc1(wt/mut); Tuber; Tuberous sclerosis complex; central nervous system; cerebral spinal fluid; eIF4E-binding protein 1; electroencephalography; embryonic day; fl; floxed; floxed Tsc1 alleles (transgenic mice); floxed and mutant Tsc1 alleles; focal cortical dysplasias; fragile X mental retardation protein; fragile X syndrome; glial fibrillary acidic protein; hgfap; human gfap; in utero electroporation; inducible Cre; lateral ventricle; long-term depression; long-term potentiation; loss of heterozygosity; mGluR-LTD; mTOR; mTOR complex 1 or 2; mTORC1 or mTORC2; magnetic resonance imaging; mammalian Target of Rapamycin; metabotropic glutamate receptor class I long term depression; mgfap; mouse gfap; p70 S6 Kinase 1; postnatal day; protein phosphatase 2A; retinal ganglion cells; subependymal giant cell astrocytoma; subependymal nodules; subependymal zone; tuberous sclerosis complex; wildtype and mutant Tsc1 alleles