Altered glutamate release in the dorsal striatum of the MitoPark mouse model of Parkinson's disease.
Altered glutamate release in the dorsal striatum of the MitoPark mouse model of Parkinson's disease.
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DOI：
10.1016/j.brainres.2016.09.025
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发表时间：
2016-11-15
期刊：
影响因子：
2.9
通讯作者：
Boger HA
中科院分区：
文献类型：
--
作者：
Farrand AQ;Gregory RA;Bäckman CM;Helke KL;Boger HA
线粒体功能障碍与帕金森病（PD）中多巴胺（DA）神经元的变性有关。此外，利用神经毒素如6-羟基多巴胺和1-甲基-4-苯基-1，2，3，6-四氢吡啶的PD动物模型已经表明，这些毒素通过靶向电子传递链的复合物I破坏线粒体呼吸，从而损害这些模型中的DA神经元。创建MitoPark小鼠模型以模拟在PD患者的DA系统中观察到的线粒体功能障碍。这些小鼠表现出与PD相同的表型特征，包括运动功能和DA能系统随年龄的加速下降。以前，这些小鼠对L-多巴治疗有反应，并随着年龄的增长发展为L-多巴诱导的运动障碍（LID）。参与LID形成的一个潜在机制是由于黑质纹状体DA神经传递减少导致基底神经节神经回路改变，导致背侧纹状体释放更多谷氨酸。因此，本研究的重点是评估在黑质纹状体DA已经退化的年龄的MitoPark小鼠背侧纹状体中谷氨酸神经传递的各种指标。在28周龄时，与对照小鼠相比，MitoPark小鼠在KCl刺激后背侧纹状体中的谷氨酸释放更大。此外，MitoPark小鼠的摄取动力学较慢。这些发现与谷氨酸再摄取转运蛋白GLT-1的表达减少相结合，从而提供了适合谷氨酸兴奋性毒性事件的环境，导致这些小鼠的生理功能改变。
Mitochondrial dysfunction has been implicated in the degeneration of dopamine (DA) neurons in Parkinson’s disease (PD). In addition, animal models of PD utilizing neurotoxins, such as 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, have shown that these toxins disrupt mitochondrial respiration by targeting complex I of the electron transport chain, thereby impairing DA neurons in these models. A MitoPark mouse model was created to mimic the mitochondrial dysfunction observed in the DA system of PD patients. These mice display the same phenotypic characteristics as PD, including accelerated decline in motor function and DAergic systems with age. Previously, these mice have responded to L-Dopa treatment and develop L-Dopa induced dyskinesia (LID) as they age. A potential mechanism involved in the formation of LID is greater glutamate release into the dorsal striatum as a result of altered basal ganglia neurocircuitry due to reduced nigrostriatal DA neurotransmission. Therefore, the focus of this study was to assess various indicators of glutamate neurotransmission in the dorsal striatum of MitoPark mice at an age in which nigrostriatal DA has degenerated. At 28 weeks of age, MitoPark mice had, upon KCl stimulation, greater glutamate release in the dorsal striatum compared to control mice. In addition, uptake kinetics were slower in MitoPark mice. These findings were coupled with reduced expression of the glutamate re-uptake transporter, GLT-1, thus providing an environment suitable for glutamate excitotoxic events, leading to altered physiological function in these mice.
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DOI：
10.1146/annurev.pharmtox.011008.145533
发表时间：
2010
影响因子：
12.5
作者：
Niswender CM;Conn PJ
通讯作者：
Conn PJ
影响因子：
3.9
作者：
Misonou, Y;Asahi, M;Taniguchi, N
通讯作者：
Taniguchi, N
DOI：
10.1523/jneurosci.3278-12.2013
发表时间：
2013-05-29
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Fischer KD;Houston AC;Rebec GV
通讯作者：
Rebec GV
影响因子：
4.7
作者：
Nicoletti, E.;Bockaert, J.;Collingridge, G. L.;Conn, P. J.;Ferraguti, F.;Schoepp, D. D.;Wroblewski, J. T.;Pin, J. P.
通讯作者：
Pin, J. P.
影响因子：
4.7
作者：
Day, BK;Pomerleau, F;Gerhardt, GA
通讯作者：
Gerhardt, GA