Anatomical localization of Cav3.1 calcium channels and electrophysiological effects of T-type calcium channel blockade in the motor thalamus of MPTP-treated monkeys

• Published in: Journal of neurophysiology Vol. 115; no. 1; pp. 470 - 485
• Main Authors: Devergnas, Annaelle, Chen, Erdong, Ma, Yuxian, Hamada, Ikuma, Pittard, Damien, Kammermeier, Stefan, Mullin, Ariana P, Faundez, Victor, Lindsley, Craig W, Jones, Carrie, Smith, Yoland, Wichmann, Thomas
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01-01-2016
• Subjects: Action Potentials - drug effects; Animals; Azabicyclo Compounds - administration & dosage; Azabicyclo Compounds - pharmacology; Basal Ganglia - metabolism; Basal Ganglia - ultrastructure; Benzamides - administration & dosage; Benzamides - pharmacology; Calcium Channel Blockers - administration & dosage; Calcium Channels, T-Type - metabolism; Calcium Channels, T-Type - physiology; Dendrites - metabolism; Dendrites - ultrastructure; Macaca mulatta; Nervous System Pathophysiology; Neural Pathways - drug effects; Neural Pathways - physiology; Neural Pathways - ultrastructure; Neurons - drug effects; Neurons - physiology; Parkinsonian Disorders - metabolism; Parkinsonian Disorders - physiopathology; Thalamus - drug effects; Thalamus - metabolism; Thalamus - physiology; Thalamus - ultrastructure; Parkinsonism; rebound burst; nondopaminergic therapy; T-type calcium channel
• ISSN: 0022-3077; 1522-1598
• DOI: 10.1152/jn.00858.2015

Conventional anti-Parkinsonian dopamine replacement therapy is often complicated by side effects that limit the use of these medications. There is a continuing need to develop nondopaminergic approaches to treat Parkinsonism. One such approach is to use medications that normalize dopamine depletion-related firing abnormalities in the basal ganglia-thalamocortical circuitry. In this study, we assessed the potential of a specific T-type calcium channel blocker (ML218) to eliminate pathologic burst patterns of firing in the basal ganglia-receiving territory of the motor thalamus in Parkinsonian monkeys. We also carried out an anatomical study, demonstrating that the immunoreactivity for T-type calcium channels is strongly expressed in the motor thalamus in normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. At the electron microscopic level, dendrites accounted for >90% of all tissue elements that were immunoreactive for voltage-gated calcium channel, type 3.2-containing T-type calcium channels in normal and Parkinsonian monkeys. Subsequent in vivo electrophysiologic studies in awake MPTP-treated Parkinsonian monkeys demonstrated that intrathalamic microinjections of ML218 (0.5 μl of a 2.5-mM solution, injected at 0.1-0.2 μl/min) partially normalized the thalamic activity by reducing the proportion of rebound bursts and increasing the proportion of spikes in non-rebound bursts. The drug also attenuated oscillatory activity in the 3-13-Hz frequency range and increased gamma frequency oscillations. However, ML218 did not normalize Parkinsonism-related changes in firing rates and oscillatory activity in the beta frequency range. Whereas the described changes are promising, a more complete assessment of the cellular and behavioral effects of ML218 (or similar drugs) is needed for a full appraisal of their anti-Parkinsonian potential.