Subthalamic discharges as a causal determinant of parkinsonian motor deficits

Tai, Chun‐Hwei; Pan, Ming‐Kai; Lin, Jyh-Woei; Huang, Cong-Hui; Yang, Ya‐Chin; Kuo, Chung‐Chin

doi:10.1002/ana.23618

Cited by 31 publications

(60 citation statements)

References 41 publications

(87 reference statements)

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“…In fact, we have documented that DBS can generate very different or even opposite effects with different pulse durations but fixed stimulation frequencies (25). Moreover, direct-current stimulation of the STN, obviously a rate-independent process, has a very strong therapeutic effect in parkinsonian rats (26). These findings suggest that the rate-independent mechanisms of stimulation, such as modulation of membrane potential and suppression of subthalamic bursts (25,26), may play a major role in the therapeutic basis of DBS.…”

Section: Discussionmentioning

confidence: 96%

“…The dependence on glutamatergic cortical input would therefore be more pronounced in PD, a condition in which subthalamic neurons are more hyperpolarized due to the overexpression of NMDA receptor-dependent K-ATP channels under chronic dopamine depletion (45,46). The hyperpolarized state could result in increased availability of the T-type calcium channel (25,42) and cause a much higher prevalence of cortically driven subthalamic bursts (26). The full development of the foregoing serial changes requires chronic dopamine depletion (45), which explains why subthalamic bursts (18,20), cortico-subthalamic synchronization (10), and intrasubthalamic synchronization (10) all take several days or longer to develop.…”

Section: Discussionmentioning

confidence: 99%

“…Excessive subthalamic bursts (9,(18)(19)(20) and abnormal cortico-subthalamic beta synchronization (10,(21)(22)(23)(24) are 2 specific landmarks directly linked to PD in both patients (10,19,23,24) and rodent models (9,18,(20)(21)(22). An increase in subthalamic burst discharges has been shown to play a causal role in hypokinetic symptoms (25,26). Injection of T-type calcium channel antagonists or depolarizing currents into the STN readily decreases subthalamic burst discharges and remedies parkinsonian locomotor deficits (25,26).…”

Section: Introductionmentioning

confidence: 99%

“…An increase in subthalamic burst discharges has been shown to play a causal role in hypokinetic symptoms (25,26). Injection of T-type calcium channel antagonists or depolarizing currents into the STN readily decreases subthalamic burst discharges and remedies parkinsonian locomotor deficits (25,26). Hyperpolarization of subthalamic neurons, on the other hand, increases burst discharges and renders a normal animal hypokinetic (26).…”

Section: Introductionmentioning

confidence: 99%

“…Injection of T-type calcium channel antagonists or depolarizing currents into the STN readily decreases subthalamic burst discharges and remedies parkinsonian locomotor deficits (25,26). Hyperpolarization of subthalamic neurons, on the other hand, increases burst discharges and renders a normal animal hypokinetic (26). Corticosubthalamic beta synchronization, another electrophysiological landmark in PD, is also correlated with hypokinetic movements and can be suppressed by dopaminergic agents (21,23).…”

Section: Introductionmentioning

confidence: 99%

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Deranged NMDAergic cortico-subthalamic transmission underlies parkinsonian motor deficits

Pan¹,

Tai²,

Liu³

et al. 2014

J. Clin. Invest.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Deranged NMDAergic cortico-subthalamic transmission underlies parkinsonian motor deficits

Pan¹,

Tai²,

Liu³

et al. 2014

J. Clin. Invest.

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T‐type calcium channels as therapeutic targets in essential tremor and Parkinson's disease

Matthews

Puryear

Correia

et al. 2023

Ann Clin Transl Neurol

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Neuronal action potential firing patterns are key components of healthy brain function. Importantly, restoring dysregulated neuronal firing patterns has the potential to be a promising strategy in the development of novel therapeutics for disorders of the central nervous system. Here, we review the pathophysiology of essential tremor and Parkinson's disease, the two most common movement disorders, with a focus on mechanisms underlying the genesis of abnormal firing patterns in the implicated neural circuits. Aberrant burst firing of neurons in the cerebello-thalamo-cortical and basal ganglia-thalamo-cortical circuits contribute to the clinical symptoms of essential tremor and Parkinson's disease, respectively, and T-type calcium channels play a key role in regulating this activity in both the disorders. Accordingly, modulating T-type calcium channel activity has received attention as a potentially promising therapeutic approach to normalize abnormal burst firing in these diseases. In this review, we explore the evidence supporting the theory that T-type calcium channel blockers can ameliorate the pathophysiologic mechanisms underlying essential tremor and Parkinson's disease, furthering the case for clinical investigation of these compounds. We conclude with key considerations for future investigational efforts, providing a critical framework for the development of much needed agents capable of targeting the dysfunctional circuitry underlying movement disorders such as essential tremor, Parkinson's disease, and beyond.

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Differential calcium channel‐mediated dopaminergic modulation in the subthalamonigral synapse

Robles‐Gómez¹,

Vega

Florán

et al. 2020

Synapse

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Dopamine (DA) modulates basal ganglia (BG) activity for initiation and execution of goal‐directed movements and habits. While most studies are aimed to striatal function, the cellular and molecular mechanisms underlying dopaminergic regulation in other nuclei of the BG are not well understood. Therefore, we set to analyze the dopaminergic modulation occurring in subthalamo‐nigral synapse, in both pars compacta (SNc) and pars reticulata (SNr) neurons, because these synapses are important for the integration of information previously processed in striatum and globus pallidus. In this study, electrophysiological and pharmacological evidence of dopaminergic modulation on glutamate release through calcium channels is presented. Using paired pulse ratio (PPR) measurements and selective blockers of these ionic channels, together with agonists and antagonists of DA D2‐like receptors, we found that blockade of the CaV3 family occludes the presynaptic inhibition produced by the activation of DA receptors pharmacologically profiled as D3‐type in the STh‐SNc synapses. On the contrast, the blockade of CaV2 channels, but not CaV3, occlude with the effect of the D3 agonist, PD 128907, in the STh‐SNr synapse. The functional role of this differential distribution of calcium channels that modulate the release of glutamate in the SN implies a fine adjustment of firing for both classes of neurons. Dopaminergic neurons of the SNc establish a DA tone within the SN based on the excitatory/inhibitory inputs; such tone may contribute to processing information from subthalamic nucleus and could also be involved in pathological DA depletion that drives hyperexcitation of SNr neurons.

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Subthalamic discharges as a causal determinant of parkinsonian motor deficits

Cited by 31 publications

References 41 publications

Deranged NMDAergic cortico-subthalamic transmission underlies parkinsonian motor deficits

Deranged NMDAergic cortico-subthalamic transmission underlies parkinsonian motor deficits

T‐type calcium channels as therapeutic targets in essential tremor and Parkinson's disease

Differential calcium channel‐mediated dopaminergic modulation in the subthalamonigral synapse

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