Facilitation of GluN2C-containing NMDA receptors in the external globus pallidus increases firing of fast spiking neurons and improves motor function in a hemiparkinsonian mouse model.
Facilitation of GluN2C-containing NMDA receptors in the external globus pallidus increases firing of fast spiking neurons and improves motor function in a hemiparkinsonian mouse model.
复制标题
在偏侧帕金森病小鼠模型中，促进外部苍白球中含GluN2C的NMDA受体增加快速尖峰神经元的放电并改善运动功能。
DOI：
10.1016/j.nbd.2021.105254
复制
发表时间：
2021-03
影响因子：
6.1
通讯作者：
Dravid SM
中科院分区：
文献类型：
--
作者：
Liu J;Shelkar GP;Sarode LP;Gawande DY;Zhao F;Clausen RP;Ugale RR;Dravid SM
苍白球外侧（GPe）是基底神经节回路中参与运动控制的核团。最近的研究表明GPe细胞类型在帕金森综合征中的关键作用。已经发现，特别是增加GPe中的小清蛋白（PV）神经元的功能有助于帕金森病（PD）小鼠模型的运动功能。NMDA受体对GPe功能的贡献的知识是有限的。在这里，我们表明，快速尖峰神经元的GPe表达NMDA受体电流敏感的GluN 2C/GluN 2D-选择性抑制剂和甘氨酸位点激动剂具有更高的功效，在GluN 2C-含受体。此外，使用一种新的报告模型，我们证明了GluN 2C亚基的表达在PV神经元的GPe项目丘脑底核。GluN 2D亚基也定位于GPe的PV神经元。GluN 2C亚基的消融不影响快速发放神经元的自发放电。与此相反，使用甘氨酸位点NMDA受体激动剂，D-环丝氨酸（DCS）或AICP促进含GluN 2C受体的功能，以GluN 2C依赖的方式增加PV神经元的自发放电频率。最后，我们证明，局部输注DCS或AICP到GPe改善运动功能的PD小鼠模型。总之，这些结果表明，GluN 2C-含有受体和潜在的GluN 2D-含有受体的GPe可以作为一个治疗目标，以减轻运动功能障碍的PD和相关疾病。
Globus pallidus externa (GPe) is a nucleus in the basal ganglia circuitry involved in the control of movement. Recent studies have demonstrated a critical role of GPe cell types in Parkinsonism. Specifically increasing the function of parvalbumin (PV) neurons in the GPe has been found to facilitate motor function in a mouse model of Parkinson’s disease (PD). The knowledge of contribution of NMDA receptors to GPe function is limited. Here, we demonstrate that fast spiking neurons in the GPe express NMDA receptor currents sensitive to GluN2C/GluN2D-selective inhibitors and glycine site agonist with higher efficacy at GluN2C-containing receptors. Furthermore, using a novel reporter model, we demonstrate the expression of GluN2C subunits in PV neurons in the GPe which project to subthalamic nuclei. GluN2D subunit was also found to localize to PV neurons in GPe. Ablation of GluN2C subunit does not affect spontaneous firing of fast spiking neurons. In contrast, facilitating the function of GluN2C-containing receptors using glycine-site NMDA receptor agonists, D-cycloserine (DCS) or AICP, increased the spontaneous firing frequency of PV neurons in a GluN2C-dependent manner. Finally, we demonstrate that local infusion of DCS or AICP into the GPe improved motor function in a mouse model of PD. Together, these results demonstrate that GluN2C-containing receptors and potentially GluN2D-containing receptors in the GPe may serve as a therapeutic target for alleviating motor dysfunction in PD and related disorders.
登录
查看更多内容
影响因子：
4.7
作者：
Gupta SC;Yadav R;Pavuluri R;Morley BJ;Stairs DJ;Dravid SM
通讯作者：
Dravid SM
影响因子：
4.7
作者：
COSTALL, B;NAYLOR, RJ;OLLEY, JE
通讯作者：
OLLEY, JE
影响因子：
3.6
作者：
Liu, Jinxu;Shelkar, Gajanan P.;Dravid, Shashank M.
通讯作者：
Dravid, Shashank M.
影响因子：
5.3
作者：
Holgado, Alejo J. Nevado;Terry, John R.;Bogacz, Rafal
通讯作者：
Bogacz, Rafal
影响因子：
4.4
作者：
Alsaad HA;DeKorver NW;Mao Z;Dravid SM;Arikkath J;Monaghan DT
通讯作者：
Monaghan DT