A circuitry and biochemical basis for tuberous sclerosis symptoms: from epilepsy to neurocognitive deficits

• Published in: International journal of developmental neuroscience Vol. 31; no. 7; pp. 667 - 678
• Main Authors: Feliciano, David M., Lin, Tiffany V., Hartman, Nathaniel W., Bartley, Christopher M., Kubera, Cathryn, Hsieh, Lawrence, Lafourcade, Carlos, O’Keefe, Rachel A., Bordey, Angelique
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01.11.2013
• Subjects: Animals; Autism; Central Nervous System - metabolism; Central Nervous System - pathology; Cognition Disorders - etiology; Cognition Disorders - genetics; Dendrite; Differentiation; Disease Models, Animal; Epilepsy; Epilepsy - etiology; Epilepsy - genetics; FMRP; Humans; Mental retardation; Mice; Migration; mTOR; Neurogenesis; Progenitor cell; SEGA; Seizures; Spine; Stem cell; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Tuber; Tuberous Sclerosis - complications; Tuberous Sclerosis - genetics; Tuberous Sclerosis - pathology; Tuberous sclerosis complex; Spine; FMR1; Migration; LV; SEGA; mgfap; FCDs; IUE; mTOR; Tuber; RGCs; LOH; TSC; EEG; SynI-Cre; TSC1 or TSC2; GAP; LTD; SEN; FXS; Tsc1fl/mut; E; MRI; fl; Epilepsy; Stem cell; CNS; LTP; SEZ; Mental retardation; Neurogenesis; P; Tsc1fl/fl; Rheb; CSF; mTORC1 or mTORC2; hgfap; Seizures; Tsc1wt/mut; FMRP; mGluR-LTD; PP2A; GFAP; S6K1; Dendrite; Autism; CreERT2; 4E-BP1; Differentiation; Tuberous sclerosis complex; Progenitor cell; human gfap; subependymal giant cell astrocytoma; Synapsin I promoter-driven Cre; embryonic day; postnatal day; GTPase activating protein; lateral ventricle; wildtype and mutant Tsc1 alleles; long-term depression; cerebral spinal fluid; mammalian Target of Rapamycin; floxed Tsc1 alleles (transgenic mice); central nervous system; floxed and mutant Tsc1 alleles; FMRP gene; floxed; metabotropic glutamate receptor class I long term depression; glial fibrillary acidic protein; p70 S6 Kinase 1; long-term potentiation; eIF4E-binding protein 1; Tsc1(wt/mut); magnetic resonance imaging; fragile X syndrome; mTOR complex 1 or 2; inducible Cre; subependymal zone; protein phosphatase 2A; Ras homolog enriched in brain; retinal ganglion cells; fragile X mental retardation protein; focal cortical dysplasias; loss of heterozygosity; electroencephalography; Tsc1(fl/mut); TSC gene 1 or gene 2; in utero electroporation; Tsc1(fl/fl); subependymal nodules; mouse gfap
• ISSN: 0736-5748; 1873-474X
• DOI: 10.1016/j.ijdevneu.2013.02.008

► Generation of cortical tuber-like lesions using in utero electroporation in mutant Tsc1 mice. ► Increased mTOR activity altered neurogenesis and circuit formation. ► Circuit dysfunction and biochemical dysregulation at synapses may account for cognitive and psychiatric impairments in tuberous sclerosis complex. 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.