Deranged NMDAergic cortico-subthalamic transmission underlies parkinsonian motor deficits
Ming-Kai Pan, … , Wen-Sung Lai, Chung-Chin Kuo
Ming-Kai Pan, … , Wen-Sung Lai, Chung-Chin Kuo
Published September 9, 2014
Citation Information: J Clin Invest. 2014;124(10):4629-4641. https://doi.org/10.1172/JCI75587.
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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 4

Effect of glutamate receptor antagonists on cortico-subthalamic beta synchronization.

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Effect of glutamate receptor antagonists on cortico-subthalamic beta syn...
Electrical activity in the low-frequency range was simultaneously recorded in the premotor cortex and STN, and frequency-dependent synchronizations were quantified by coherence analysis. (A) Raw sweeps of electrical activity simultaneously recorded in the premotor cortex and STN. (B) Time-frequency coherence plot of cortico-subthalamic synchronization. Subthalamic AP5 microinfusion started at 780 seconds (13 minutes) and lasted 300 seconds (5 minutes; gray bar at top of the plot). The total recording lasted 1 hour. Note the band of synchronization at beta frequencies (20–40 Hz) at baseline and that AP5 readily abolished beta synchronization. (C) CGS has an effect similar to that of AP5. (D) CNQX did not change the coherence in beta frequencies. (E) There was no synchronization of beta frequencies in a normal rat. (F) Quantitative measurement of coherence of beta frequencies. Coherence was significantly different between normal and parkinsonian rats (n = 13 different rats for each group; P = 0.001). (G) Quantitative measurement of the drug effect in parkinsonian rats. Coherence of beta frequencies was significantly suppressed by AP5 (n = 12, P = 0.002) and CGS (n = 9, P = 0.008), while CNQX (n = 8, P = 0.575) did not have such an effect. Statistical analyses were performed using a nonparametric Wilcoxon signed-rank test. Data represent the mean ± SEM. **P < 0.01.