Reduced juvenile long-term depression in tuberous sclerosis complex is mitigated in adults by compensatory recruitment of mGluR5 and Erk signaling.
Reduced juvenile long-term depression in tuberous sclerosis complex is mitigated in adults by compensatory recruitment of mGluR5 and Erk signaling.
复制标题
DOI：
10.1371/journal.pbio.1001627
复制
发表时间：
2013
期刊：
影响因子：
9.8
通讯作者：
Roopra A
中科院分区：
文献类型：
--
作者：
Potter WB;Basu T;O'Riordan KJ;Kirchner A;Rutecki P;Burger C;Roopra A
人类遗传性疾病结节性硬化症的小鼠模型未能经历mGluR 5表达的发育下调和Erk信号传导的激活，这可能有助于这种疾病中的异常可塑性和癫痫。多发性硬化症（TSC）是一种多系统遗传性疾病，表现为精神发育迟滞、肿瘤形成、自闭症和癫痫。通过雷帕霉素（mTOR）通路的哺乳动物靶点的增强的信号传导参与TSC病理学，然而仍不清楚其他信号传导通路如何被干扰并促成疾病症状。最近在TSC突变小鼠中报道了减少的长期抑郁症（LTD）。我们发现，尽管LTD减少是幼年突变海马的一个特征，但成年海马中代谢型谷氨酸受体5和组成性激活的Erk信号转导的表达增加驱动了LTD的野生型水平。mGluR 5和Erk的增加导致成年小鼠CA 1海马中新的mTOR非依赖性LTD，并有助于海马体TSC 2 +/− CA 3区域癫痫样爆发活动的发展。抑制mGluR 5或Erk信号传导可恢复LTD的适当mTOR依赖性，并显著减少TSC 2 +/−海马切片中的癫痫样爆发。我们还报告说，成年TSC 2 +/−小鼠表现出一种微妙的持续行为表型，这种表型被mGluR 5拮抗作用消除。这些发现强调了以发育阶段特异性方式调节mGluR 5-Erk通路以治疗TSC的潜力。多发性硬化症（TSC）是一种遗传性疾病，每6,000人中就有1人患有这种疾病，它是由两种基因之一（TSC 1或TSC 2）突变引起的。TSC患者患有许多神经元症状，包括不同程度的自闭症，精神发育迟滞和癫痫，后者在生命的第一年内发现超过80%的病例。在用于模拟该疾病的TSC突变小鼠中，大脑中称为海马体的区域未能经历长期抑郁（LTD），这是一种对学习和记忆至关重要的神经元过程。我们发现，虽然这是在幼年突变小鼠的情况下，成年小鼠似乎已经固定了这种赤字。“修复”涉及到mGluR 5和Erk信号通路的增加。虽然增加mGluR 5和Erk信号向外修复的问题，减少LTD在成年期，它使大脑不敏感的线索和输入，通常工作，以控制LTD。此外，海马在成年TSC小鼠容易癫痫发作和受损的学习和记忆任务。我们发现，针对mGluR 5或Erk信号的药物可以修复兴奋性和学习缺陷的问题。
A mouse model of the human genetic disorder tuberous sclerosis complex fails to undergo developmental down-regulation of mGluR5 expression and activation of Erk signaling, probably contributing to the aberrant plasticity and epilepsy in this disease. Tuberous sclerosis complex (TSC) is a multisystem genetic disease that manifests with mental retardation, tumor formation, autism, and epilepsy. Heightened signaling through the mammalian target of rapamycin (mTOR) pathway is involved in TSC pathology, however it remains unclear how other signaling pathways are perturbed and contribute to disease symptoms. Reduced long-term depression (LTD) was recently reported in TSC mutant mice. We find that although reduced LTD is a feature of the juvenile mutant hippocampus, heightened expression of metabotropic glutamate receptor 5 and constitutively activated Erk signaling in the adult hippocampus drives wild-type levels of LTD. Increased mGluR5 and Erk results in a novel mTOR-independent LTD in CA1 hippocampus of adult mice, and contributes to the development of epileptiform bursting activity in the TSC2+/− CA3 region of the hippocampus. Inhibition of mGluR5 or Erk signaling restores appropriate mTOR-dependence to LTD, and significantly reduces epileptiform bursting in TSC2+/− hippocampal slices. We also report that adult TSC2+/− mice exhibit a subtle perseverative behavioral phenotype that is eliminated by mGluR5 antagonism. These findings highlight the potential of modulating the mGluR5-Erk pathway in a developmental stage-specific manner to treat TSC. Tuberous sclerosis complex (TSC) is a genetic disorder that afflicts around 1 in 6,000 people and results from a mutation in one of two genes, TSC1 or TSC2. TSC patients suffer a number of neuronal symptoms including various degrees of autism, mental retardation, and epilepsy, the latter found in more than 80% of cases within the first year of life. In the TSC mutant mice that are used to model the disease, a region of the brain called the hippocampus fails to undergo long-term depression (LTD), a neuronal process that is important for learning and memory. We find that while this is the case in juvenile mutant mice, adult mice appear to have fixed this deficit. The “fix” involves the ramping up of signaling pathways involving mGluR5 and Erk. Although increased mGluR5 and Erk signaling outwardly fixes the problem of diminished LTD in adulthood, it renders the brain insensitive to the cues and inputs that normally work to control LTD. Moreover, the hippocampus in adult TSC mice is prone to seizures and impaired in learning and memory tasks. We find that drugs that target mGluR5 or Erk signaling repair the problems with excitability and learning deficits.
登录
查看更多内容
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：
64.8
作者：
Ango, F;Prézeau, L;Fagni, L
通讯作者：
Fagni, L
影响因子：
56.9
作者：
Huber, KM;Kayser, MS;Bear, MF
通讯作者：
Bear, MF
影响因子：
2.9
作者：
Abbas, Abdul-Karim;Dozmorov, Mikhail;Wigstrom, Holger
通讯作者：
Wigstrom, Holger
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