Department of Physiology and Pharmacology, Section of Molecular Neurophysiology, The Karolinska Institute, Stockholm, Sweden.
CNS Neurosci Ther. 2018 Feb;24(2):144-153. doi: 10.1111/cns.12784. Epub 2017 Dec 11.
To investigate if CIQ, a positive allosteric modulator of N-methyl-d-aspartate receptors (NMDARs) containing GluN2C/D subunits, rescues the loss of long-term potentiation (LTP) and forelimb-use asymmetry in a mouse model of Parkinson's disease (PD).
We have used electrophysiology in brain slices and the cylinder test to examine the effect of CIQ on glutamatergic synaptic transmission, synaptic plasticity, and forelimb-use in the unilateral 6-hydroxydopamine-lesion mouse model of PD.
CIQ, applied in the perfusion solution, reversibly reduced glutamatergic synaptic transmission in the dopamine-depleted striatum and had no effect in the dopamine-intact striatum. LTP, a dopamine- and NMDAR-dependent form of synaptic plasticity, was induced in the dopamine-intact striatum but was lost in the dopamine-depleted striatum. This impaired LTP was restored in the presence of CIQ applied in the perfusion solution. This treatment, however, prevented LTP induction in control slices. In brain slices from mice which received single and chronic intraperitoneal injections of CIQ, LTP was restored in the dopamine-depleted striatum and unaffected in the dopamine-intact striatum. Forelimb-use asymmetry, a test which assesses deficits in paw usage in the unilateral lesion model of PD, was reversed by systemic chronic treatment with CIQ.
A positive allosteric modulator of GluN2C/D-containing NMDARs rescues LTP and forelimb-use asymmetry in a mouse model of PD. This study proposes GluN2D as a potential candidate for therapeutic intervention in PD.
研究 CIQ（一种含 GluN2C/D 亚基的 N-甲基-D-天冬氨酸受体（NMDAR）正变构调节剂）是否能挽救帕金森病（PD）小鼠模型中长时程增强（LTP）和前肢使用不对称的丧失。
我们使用脑片电生理学和圆筒测试来研究 CIQ 对谷氨酸能突触传递、突触可塑性以及单侧 6-羟多巴胺损伤 PD 小鼠模型中前肢使用的影响。
CIQ 在灌流液中的应用可逆转多巴胺耗竭纹状体中的谷氨酸能突触传递，而对多巴胺完整纹状体无影响。LTP 是一种多巴胺和 NMDAR 依赖性的突触可塑性形式，在多巴胺完整纹状体中诱导，但在多巴胺耗竭纹状体中丧失。这种受损的 LTP 在 CIQ 存在下的灌流液中得到恢复。然而，这种治疗方法阻止了对照切片中的 LTP 诱导。在接受单次和慢性腹腔注射 CIQ 的小鼠脑片中，LTP 在多巴胺耗竭纹状体中得到恢复，而在多巴胺完整纹状体中不受影响。前肢使用不对称，是评估 PD 单侧损伤模型中爪子使用缺陷的测试，通过 CIQ 的系统慢性治疗得到逆转。
含 GluN2C/D 的 NMDAR 的正变构调节剂挽救了 PD 小鼠模型中的 LTP 和前肢使用不对称。这项研究提出 GluN2D 可能是 PD 治疗干预的潜在候选物。
