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

International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience ·Vol. 31 ·No. 7 ·2014-06-27

Feliciano David M, Lin Tiffany V, Hartman Nathaniel W, Bartley Christopher M, Kubera Cathryn, Hsieh Lawrence, Lafourcade Carlos, O'Keefe Rachel A, Bordey Angelique

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.

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

Article Info

Journal

International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience

Abbr.

Int J Dev Neurosci

ISSN

0736-5748

Published

2014-06-27

Indexed

2013-11-15

Updated

2016-10-19

Language

English

Country/Region

England

NLM ID

8401784

External Links

PubMed source View journal details

Analysis Services

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

Contact

WeChat Official Account