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Front. Cell. Neurosci. | doi: 10.3389/fncel.2019.00009

Electrical Abnormalities in Dopaminergic Neurons of the Substantia Nigra in Mice With an Aromatic L-amino Acid Decarboxylase Deficiency

 Shih-Yin Ho1, 2,  Yin-Hsiu Chien3, 4,  Li-Kai Tsai1,  Shin-ichi Muramatsu5, 6, Wuh-Liang Hwu3, 4, Horng-Huei Liou1, 2, 7* and  Ni-Chung Lee1, 3*
  • 1Department of Neurology, National Taiwan University Hospital, Taiwan
  • 2Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taiwan
  • 3Department of Medical Genetics, National Taiwan University Hospital, Taiwan
  • 4Department of Pediatrics, National Taiwan University Hospital, Taiwan
  • 5Jichi Medical University, Japan
  • 6Center for Gene and Cell Therapy, Institute of Medical Science, University of Tokyo, Japan
  • 7National Taiwan University Hospital Yunlin Branch, Taiwan

Aromatic L-acid decarboxylase (AADC) deficiency causes severe motor disturbances in affected children. A putamen-targeted gene therapy improves the motor function of patients. The present study investigated the electrical properties of dopaminergic (DA) neurons in the substantia nigra compacta (SNc) of mice with an AADC deficiency (DdcKI). The basal firing of DA neurons, which determines DA release in the putamen, was abnormal in the DdcKI mice, including a low frequency and irregular firing pattern, because of a decrease in the after-hyperpolarization (AHP) amplitude of action potentials. The frequency of spontaneous excitatory postsynaptic currents (sEPSCs) increased and that of spontaneous inhibitory postsynaptic currents (sIPSCs) decreased in the SNc DA neurons from the DdcKI mice, suggesting an elevation in glutamatergic excitatory stimuli and a reduction in GABAergic inhibitory stimuli, respectively. Altered expression patterns of genes encoding receptors and channels were also observed in the DdcKI mice. Administration of a widespread neuron-specific gene therapy to the brains of the DdcKI mice partially corrected these electric abnormalities. The overexcitability of SNc DA neurons in the presence of generalized dopamine deficiency likely underlies the occurrence of motor disturbances.

Keywords: Aromatic L-acid decarboxylase, Motor disturbances, after-hyperpolarization (AHP), Substantia Nigra, Gene Therapy, dopaminergic neuron

Received: 30 Oct 2018; Accepted: 10 Jan 2019.

Edited by:

Sergey M. Korogod, Bogomoletz Institute of Physiology, Ukraine

Reviewed by:

Amiel Rosenkranz, Rosalind Franklin University of Medicine and Science, United States
Paul G. Overton, University of Sheffield, United Kingdom  

Copyright: © 2019 Ho, Chien, Tsai, Muramatsu, Hwu, Liou and Lee. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
MD, PhD. Horng-Huei Liou, Department of Neurology, National Taiwan University Hospital, Taipei, 100, Taiwan,
MD, PhD. Ni-Chung Lee, Department of Neurology, National Taiwan University Hospital, Taipei, 100, Taiwan,