PMID- 23485365 OWN - NLM STAT- MEDLINE DCOM- 20140627 LR - 20220309 IS - 1873-474X (Electronic) IS - 0736-5748 (Print) IS - 0736-5748 (Linking) VI - 31 IP - 7 DP - 2013 Nov TI - A circuitry and biochemical basis for tuberous sclerosis symptoms: from epilepsy to neurocognitive deficits. PG - 667-78 LID - S0736-5748(13)00035-X [pii] LID - 10.1016/j.ijdevneu.2013.02.008 [doi] AB - 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. CI - Copyright (c) 2013 ISDN. Published by Elsevier Ltd. All rights reserved. FAU - Feliciano, David M AU - Feliciano DM AD - 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. FAU - Lin, Tiffany V AU - Lin TV FAU - Hartman, Nathaniel W AU - Hartman NW FAU - Bartley, Christopher M AU - Bartley CM FAU - Kubera, Cathryn AU - Kubera C FAU - Hsieh, Lawrence AU - Hsieh L FAU - Lafourcade, Carlos AU - Lafourcade C FAU - O'Keefe, Rachel A AU - O'Keefe RA FAU - Bordey, Angelique AU - Bordey A LA - eng GR - R01 NS062731/NS/NINDS NIH HHS/United States GR - T32 GM007205/GM/NIGMS NIH HHS/United States GR - TG T32GM07205/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. PT - Review DEP - 20130226 PL - United States TA - Int J Dev Neurosci JT - International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience JID - 8401784 RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Central Nervous System/*metabolism/pathology MH - Cognition Disorders/*etiology/genetics MH - Disease Models, Animal MH - Epilepsy/*etiology/genetics MH - Humans MH - Mice MH - TOR Serine-Threonine Kinases/genetics/metabolism MH - *Tuberous Sclerosis/complications/genetics/pathology PMC - PMC3830611 MID - NIHMS449233 OTO - NOTNLM OT - 4E-BP1 OT - Autism OT - CNS OT - CSF OT - CreERT2 OT - Dendrite OT - Differentiation OT - E OT - EEG OT - Epilepsy OT - FCDs OT - FMR1 OT - FMRP OT - FMRP gene OT - FXS OT - GAP OT - GFAP OT - GTPase activating protein OT - IUE OT - LOH OT - LTD OT - LTP OT - LV OT - MRI OT - Mental retardation OT - Migration OT - Neurogenesis OT - P OT - PP2A OT - Progenitor cell OT - RGCs OT - Ras homolog enriched in brain OT - Rheb OT - S6K1 OT - SEGA OT - SEN OT - SEZ OT - Seizures OT - Spine OT - Stem cell OT - SynI-Cre OT - Synapsin I promoter-driven Cre OT - TSC OT - TSC gene 1 or gene 2 OT - TSC1 or TSC2 OT - Tsc1(fl/fl) OT - Tsc1(fl/mut) OT - Tsc1(wt/mut) OT - Tuber OT - Tuberous sclerosis complex OT - central nervous system OT - cerebral spinal fluid OT - eIF4E-binding protein 1 OT - electroencephalography OT - embryonic day OT - fl OT - floxed OT - floxed Tsc1 alleles (transgenic mice) OT - floxed and mutant Tsc1 alleles OT - focal cortical dysplasias OT - fragile X mental retardation protein OT - fragile X syndrome OT - glial fibrillary acidic protein OT - hgfap OT - human gfap OT - in utero electroporation OT - inducible Cre OT - lateral ventricle OT - long-term depression OT - long-term potentiation OT - loss of heterozygosity OT - mGluR-LTD OT - mTOR OT - mTOR complex 1 or 2 OT - mTORC1 or mTORC2 OT - magnetic resonance imaging OT - mammalian Target of Rapamycin OT - metabotropic glutamate receptor class I long term depression OT - mgfap OT - mouse gfap OT - p70 S6 Kinase 1 OT - postnatal day OT - protein phosphatase 2A OT - retinal ganglion cells OT - subependymal giant cell astrocytoma OT - subependymal nodules OT - subependymal zone OT - tuberous sclerosis complex OT - wildtype and mutant Tsc1 alleles EDAT- 2013/03/15 06:00 MHDA- 2014/06/28 06:00 PMCR- 2014/11/01 CRDT- 2013/03/15 06:00 PHST- 2012/11/16 00:00 [received] PHST- 2013/02/15 00:00 [revised] PHST- 2013/02/18 00:00 [accepted] PHST- 2013/03/15 06:00 [entrez] PHST- 2013/03/15 06:00 [pubmed] PHST- 2014/06/28 06:00 [medline] PHST- 2014/11/01 00:00 [pmc-release] AID - S0736-5748(13)00035-X [pii] AID - 10.1016/j.ijdevneu.2013.02.008 [doi] PST - ppublish SO - Int J Dev Neurosci. 2013 Nov;31(7):667-78. doi: 10.1016/j.ijdevneu.2013.02.008. Epub 2013 Feb 26.