A role for Kalirin-7 in corticostriatal synaptic dysfunction in Huntington's disease.
A role for Kalirin-7 in corticostriatal synaptic dysfunction in Huntington's disease.
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DOI：
10.1093/hmg/ddv426
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发表时间：
2015-12
影响因子：
3.5
通讯作者：
M. Puigdellívol;Marta Cherubini;V. Brito;A. Giralt;Nuria Suelves;J. Ballesteros;Alfonsa Zamora-Moratalla;Eduardo D. Martín;B. Eipper;J. Alberch;S. Ginés
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文献类型：
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作者：
M. Puigdellívol;Marta Cherubini;V. Brito;A. Giralt;Nuria Suelves;J. Ballesteros;Alfonsa Zamora-Moratalla;Eduardo D. Martín;B. Eipper;J. Alberch;S. Ginés
认知功能障碍是亨廷顿舞蹈病（HD）的早期临床标志，在运动症状出现前几年。神经元功能障碍和皮质纹状体连接改变被认为是解释这些早期障碍的基础。然而，没有任何一种减轻认知变化的治疗方法是成功的：原因可能在于，当新疗法正在开发时，病理变化的时间顺序与变化本身一样重要。为此，使用认知障碍先于运动症状出现的HD小鼠模型变得至关重要。在这项研究中，我们展示了两种不同的HD小鼠的程序记忆和运动学习缺陷，以及在运动障碍之前的年龄。这些损伤与HD小鼠皮质纹状体长期增强（LTP）的改变、树突棘密度和突触后密度(PSD)-95的特异性减少以及脊髓蛋白阳性簇的减少有关。作为一种潜在的机制，我们描述了在HD小鼠皮层中，一种对维持兴奋性突触至关重要的rho样小gtpase的鸟嘌呤核苷酸交换因子kalin -7 （Kal7）的早期减少。支持Kal7在HD突触缺陷中的作用，Kal7的外源性表达恢复HD皮层培养中兴奋性突触的减少。总之，我们的研究结果表明，在HD患者中，皮层功能障碍先于纹状体紊乱，是早期皮质纹状体LTP和认知缺陷的基础。此外，我们发现Kal7的减少是HD皮质改变的关键因素，将Kal7作为未来治疗HD皮质纹状体功能恢复的分子靶点。
Cognitive dysfunction is an early clinical hallmark of Huntington's disease (HD) preceding the appearance of motor symptoms by several years. Neuronal dysfunction and altered corticostriatal connectivity have been postulated to be fundamental to explain these early disturbances. However, no treatments to attenuate cognitive changes have been successful: the reason may rely on the idea that the temporal sequence of pathological changes is as critical as the changes per se when new therapies are in development. To this aim, it becomes critical to use HD mouse models in which cognitive impairments appear prior to motor symptoms. In this study, we demonstrate procedural memory and motor learning deficits in two different HD mice and at ages preceding motor disturbances. These impairments are associated with altered corticostriatal long-term potentiation (LTP) and specific reduction of dendritic spine density and postsynaptic density (PSD)-95 and spinophilin-positive clusters in the cortex of HD mice. As a potential mechanism, we described an early decrease of Kalirin-7 (Kal7), a guanine-nucleotide exchange factor for Rho-like small GTPases critical to maintain excitatory synapse, in the cortex of HD mice. Supporting a role for Kal7 in HD synaptic deficits, exogenous expression of Kal7 restores the reduction of excitatory synapses in HD cortical cultures. Altogether, our results suggest that cortical dysfunction precedes striatal disturbances in HD and underlie early corticostriatal LTP and cognitive defects. Moreover, we identified diminished Kal7 as a key contributor to HD cortical alterations, placing Kal7 as a molecular target for future therapies aimed to restore corticostriatal function in HD.