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

Shih-Yin Ho,Li-Kai Tsai,Shin-Ichi Muramatsu,Wuh-Liang Hwu,Horng-Huei Liou,Yin-Hsiu Chien,Ni-Chung Lee

doi:10.3389/fncel.2019.00009

Abstract

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 (APs). The frequency of spontaneous excitatory postsynaptic currents (sEPSCs) increased and that of spontaneous inhibitory PSCs (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.

Highlights

Aromatic L-acid decarboxylase (AADC) deficiency (MIM 608643) is a rare genetic disorder caused by a deficiency in AADC activity required for the synthesis of dopamine, serotonin, and other monoamines (Brun et al, 2010)
We have previously developed a gene therapy for children with AADC deficiency using an intraputaminal injection of adeno-associated virus (AAV) type 2 vectors expressing the DDC cDNA (Hwu et al, 2012)
We previously demonstrated that DdcKI (KI) mice exhibit a profound DA deficiency, poor weight gain, and early death (Lee et al, 2013); possibly due to reduced food intake and followed by essential compounds deficiency including tryptophan that further worsen the serotonin deficiency; and gene therapy rescues these deficits (Lee et al, 2014, 2015)

Summary

Introduction

Aromatic L-acid decarboxylase (AADC) deficiency (MIM 608643) is a rare genetic disorder caused by a deficiency in AADC activity required for the synthesis of dopamine, serotonin, and other monoamines (Brun et al, 2010). Patients with a severe AADC deficiency experience hypotonia, hypokinesia, dystonia, oculogyric crisis (OGC), and developmental delays because of a dopamine deficiency in the striatum (Brun et al, 2010). Electrical Abnormalities in AADC Deficiency disturbances because of the serotonin deficiency in the brain and autonomic dysfunction caused by systemic epinephrine and norepinephrine deficiencies (Brun et al, 2010). We have previously developed a gene therapy for children with AADC deficiency using an intraputaminal injection of adeno-associated virus (AAV) type 2 vectors expressing the DDC cDNA (Hwu et al, 2012). Patients exhibited dramatic improvements in motor development and moderate improvements in emotional control and cognitive function after gene therapy (Hwu et al, 2012). The underlying cellular mechanism for the motor disturbances of AADC deficiency remains elucidative

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