A circuitry and biochemical basis for tuberous sclerosis symptoms: from epilepsy to neurocognitive deficits.
A circuitry and biochemical basis for tuberous sclerosis symptoms: from epilepsy to neurocognitive deficits.
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DOI：
10.1016/j.ijdevneu.2013.02.008
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发表时间：
2013-11
期刊：
影响因子：
--
通讯作者：
Bordey A
中科院分区：
文献类型：
--
作者：
Feliciano DM;Lin TV;Hartman NW;Bartley CM;Kubera C;Hsieh L;Lafourcade C;O'Keefe RA;Bordey A
结节性硬化症(TSC)是一种常染色体显性遗传性单基因遗传病，以多个器官良性肿瘤的形成以及脑畸形和神经元缺陷为特征。TSC是由两个基因之一TSC1和TSC2的失活突变引起的，导致哺乳动物雷帕霉素靶标(MTOR)活性增加。在这里，我们探讨了细胞结构和功能性中枢神经系统的异常，可能解释了TSC的神经学表现，特别是癫痫发作、脑积水以及认知和心理障碍。特别是，最近提出的小鼠脑损伤模型，重点是使用电穿孔技术，允许在围产期发育过程中因杂合性丢失而产生离散的损伤。皮质损伤被认为有助于癫痫的发生和认知缺陷的恶化。然而，最近有人提出，出生时携带突变的等位基因而没有杂合性丢失和相关的皮质损伤足以产生认知和神经精神问题。因此，我们将讨论mTOR高活性在神经元回路形成中的作用，以及出生时杂合子对神经元功能和突触可塑性的潜在影响，突触可塑性是学习和记忆的细胞底物。最终，TSC研究的一个主要目标是确定在TSC患者中观察到的神经表现背后的mTOR下游的细胞和分子机制，并确定新的治疗靶点，以防止脑损伤的形成和恢复神经功能。
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 heterozygote 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.
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影响因子：
6.1
作者：
Chevere-Torres, Itzamarie;Kaphzan, Hanoch;Bhattacharya, Aditi;Kang, Areum;Maki, Jordan M.;Gambello, Michael J.;Arbiser, Jack L.;Santini, Emanuela;Klann, Eric
通讯作者：
Klann, Eric
影响因子：
5.3
作者：
Banko, JL;Poulin, F;Klann, E
通讯作者：
Klann, E
影响因子：
3.5
作者：
Anderl, Stefanie;Freeland, Megan;Goto, June
通讯作者：
Goto, June
DOI：
10.1523/jneurosci.1617-11.2011
发表时间：
2011-06-15
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Bateup HS;Takasaki KT;Saulnier JL;Denefrio CL;Sabatini BL
通讯作者：
Sabatini BL
影响因子：
5.6
作者：
Cepeda C;André VM;Yamazaki I;Hauptman JS;Chen JY;Vinters HV;Mathern GW;Levine MS
通讯作者：
Levine MS