Deranged NMDAergic cortico-subthalamic transmission underlies parkinsonian motor deficits
Ming-Kai Pan, Chun-Hwei Tai, Wen-Chuan Liu, Ju-Chun Pei, Wen-Sung Lai, Chung-Chin Kuo
Ming-Kai Pan, Chun-Hwei Tai, Wen-Chuan Liu, Ju-Chun Pei, Wen-Sung Lai, Chung-Chin Kuo
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Research Article Neuroscience

Deranged NMDAergic cortico-subthalamic transmission underlies parkinsonian motor deficits

Abstract

Parkinson’s disease (PD) is the most prevalent hypokinetic movement disorder, and symptomatic PD pathogenesis has been ascribed to imbalances between the direct and indirect pathways in the basal ganglia circuitry. Here, we applied glutamate receptor blockers to the subthalamic nucleus (STN) of parkinsonian rats and evaluated locomotor behaviors via single-unit and local-field recordings. Using this model, we found that inhibition of NMDAergic cortico-subthalamic transmission ameliorates parkinsonian motor deficits without eliciting any vivid turning behavior and abolishes electrophysiological abnormalities, including excessive subthalamic bursts, cortico-subthalamic synchronization, and in situ beta synchronization in both the motor cortex and STN. Premotor cortex stimulation revealed that cortico-subthalamic transmission is deranged in PD and directly responsible for the excessive stimulation-dependent bursts and time-locked spikes in the STN, explaining the genesis of PD-associated pathological bursts and synchronization, respectively. Moreover, application of a dopaminergic agent via a microinfusion cannula localized the therapeutic effect to the STN, without correcting striatal dopamine deficiency. Finally, optogenetic overactivation and synchronization of cortico-subthalamic transmission alone sufficiently and instantaneously induced parkinsonian-associated locomotor dysfunction in normal mice. In addition to the classic theory emphasizing the direct-indirect pathways, our data suggest that deranged cortico-subthalamic transmission via the NMDA receptor also plays a central role in the pathophysiology of parkinsonian motor deficits.

Authors

Ming-Kai Pan, Chun-Hwei Tai, Wen-Chuan Liu, Ju-Chun Pei, Wen-Sung Lai, Chung-Chin Kuo

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Figure 2

Quantitative parameters of locomotor activities and asymmetrical movements in hemiparkinsonian rats.

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Quantitative parameters of locomotor activities and asymmetrical movemen...
NMDA receptor blockers AP5 (n = 13 different rats) and CGS (n = 9), AMPA receptor blocker CNQX (n = 21), a mixture of AP5 and CNQX (A + C, n = 18), and nonselective dopamine receptor agonist apomorphine (Apo, n = 13) were locally delivered to the STN. Each drug (colored bars) had a paired control with aCSF microinfusion (black bars). Movement distance (A), movement duration (B), and rearing score (C) demonstrate movement ability. Performance of the normal rats (n = 12) is also shown for reference. Rotational bias (D), head position bias (E), and net asymmetrical climbing (F) indicate asymmetrical movements due to unilateral 6-OHDA lesions. The same parameters were also documented for systemic s.c. injection of apomorphine (Apo s.c., n = 11, gray bars) and a paired control with s.c. injection of saline (white bars). Note that NMDA, but not AMPA, receptor antagonists improved all locomotor parameters and ameliorated asymmetrical motor deficits. Subthalamic apomorphine had an effect similar to that of NMDA receptor blockers. However, systemic apomorphine induced strong paradoxical movements, which included unilateral rotation (D), paradoxical head deviation (E), and worsening of asymmetrical climbing (F). Statistical analyses were performed using a nonparametric Wilcoxon signed-rank test. Data represent the mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001.