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 6

Burst firing of subthalamic single units evoked by electrical stimulation of the premotor cortex.

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Burst firing of subthalamic single units evoked by electrical stimulatio...
To avoid a fixed-frequency effect, the stimulation frequencies were pseudorandomized between 1 and 2 Hz for a total of 400 stimuli. For each stimulus, the evoked subthalamic firing activity for 150 ms was analyzed. (A) Typical sweep of a bursting unit evoked by cortical stimulation. Note the stimulation artifact at the beginning of the sweep and the following single-unit firing in a cluster. (B) Population of stimulation-responsive bursting units in parkinsonian and normal rats. 91.7% (11 of 12 units in 3 rats) of subthalamic single units in parkinsonian rats were burst generating under cortical stimulation, much higher than the 34.3% (11 of 32 units in 10 rats) seen in normal rats. (C) Time-dependent profiles of evoked subthalamic bursts in parkinsonian and normal rats. Cortical stimulation evoked excessive bursts mainly during the initial 50 ms in both parkinsonian (n = 11) and normal rats (n = 11), illustrating the stimulation-dependent nature of subthalamic bursts. (D) Evoked subthalamic bursts (at 0–50 ms) were suppressed by subthalamic infusion of AP5 into both normal (n = 7 units in 6 rats) and parkinsonian rats (n = 9 units in 5 rats). Note that the burst counts in the 50–100 ms and 100–150 ms periods were also reduced. Thus, the spontaneous cortico-subthalamic transmissions, which were not time-locked by electrical stimulation, were also suppressed by AP5. Statistics were calculated by 1-way ANOVA with Dunnett’s post-hoc correction. Data represent the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001.