Dysregulated intracellular signaling in the striatum in a pathophysiologically grounded model of Tourette syndrome.
Dysregulated intracellular signaling in the striatum in a pathophysiologically grounded model of Tourette syndrome.
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DOI：
10.1016/j.euroneuro.2014.10.007
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发表时间：
2014-12
影响因子：
5.6
通讯作者：
Pittenger, Christopher
中科院分区：
文献类型：
--
作者：
Rapanelli, Maximiliano;Frick, Luciana R.;Pogorelov, Vladimir;Ota, Kristie T.;Abbasi, Eeman;Ohtsu, Hiroshi;Pittenger, Christopher
抽动障碍产生大量的发病率，但其病理生理仍知之甚少。越来越多的证据表明，皮质-基底神经节回路的失调是抽搐发病的核心。抽动秽语综合征（TS）是抽动障碍中最严重的一种，基本上是遗传的，但致病突变一直难以捉摸。我们最近描述了一个小鼠模型，组氨酸脱羧酶（Hdc）敲除小鼠，概括了一个罕见的，高度渗透的突变，在一个单一的家庭中发现；这些小鼠表现出ts样现象学。这些动物在脑组织胺的整体缺陷和随之而来的DA在基底神经节失调。组胺调节DA的作用越来越受到重视，但这种调节的机制尚不清楚；在严重HA缺乏的情况下，适度DA升高的后果很难预测，但在Hdc敲除小鼠中了解它们可能会为TS的病理生理学提供普遍的见解。在本研究中，我们表征了该模型系统中纹状体细胞在基线和安非他明刺激后的信号通路。体内微透析证实hdl - ko小鼠DA升高。我们发现Akt及其靶点GSK3β的去磷酸化和MAPK信号级联及其靶点rpS6的激活；这些分别是DA对表达D2和d1的纹状体神经元影响的特征。引人注目的是，在两种细胞类型中，mTOR信号没有改变，这可以由DA调节。这些细胞效应有助于阐明独特验证的TS小鼠模型中的纹状体信号异常，并朝着确定抽动障碍的新潜在治疗靶点迈进。
Tic disorders produce substantial morbidity, but their pathophysiology remains poorly understood. Convergent evidence suggests that dysregulation of the cortico-basal ganglia circuitry is central to the pathogenesis of tics. Tourette syndrome (TS), the most severe end of the continuum of tic disorders, is substantially genetic, but causative mutations have been elusive. We recently described a mouse model, the histidine decarboxylase (Hdc) knockout mouse, that recapitulates a rare, highly penetrant mutation found in a single family; these mice exhibit TS-like phenomenology. These animals have a global deficit in brain histamine and a consequent dysregulation of DA in the basal ganglia. Histamine modulation of DA effects is increasingly appreciated, but the mechanisms underlying this modulation remain unclear; the consequences of modest DA elevation in the context of profound HA deficiency are difficult to predict, but understanding them in the Hdc knockout mouse may provide generalizable insights into the pathophysiology of TS. Here we characterized signaling pathways in striatal cells in this model system, at baseline and after amphetamine challenge. In vivo microdialysis confirms elevated DA in Hdc-KO mice. We find dephosphorylation of Akt and its target GSK3β and activation of the MAPK signaling cascade and its target rpS6; these are characteristic of the effects of DA on D2- and D1-expressing striatal neurons, respectively. Strikingly, there is no alteration in mTOR signaling, which can be regulated by DA in both cell types. These cellular effects help elucidate striatal signaling abnormalities in a uniquely validated mouse model of TS and move towards the identification of new potential therapeutic targets for tic disorders.
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影响因子：
14.5
作者：
Baym, C. L.;Corbett, B. A.;Bunge, S. A.
通讯作者：
Bunge, S. A.
影响因子：
30.8
作者：
Emamian, ES;Hall, D;Gogos, JA
通讯作者：
Gogos, JA
影响因子：
2
作者：
Dere, E;De Souza-Silva, MA;Huston, JP
通讯作者：
Huston, JP
DOI：
10.1523/jneurosci.3952-07.2008
发表时间：
2008-07-09
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Gerfen CR;Paletzki R;Worley P
通讯作者：
Worley P
影响因子：
64.5
作者：
Jacinto, Estela;Facchinetti, Valeria;Su, Bing
通讯作者：
Su, Bing