Abstract
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases, with approximately six million people affected worldwide. Vesicular monoamine transporter 2 (VMAT2) dysfunction has recently become a hot topic in the pathophysiology of PD, and the advent of transgenic mice has also accelerated the development of behavioral studies in animal models. However, there are only a few systematic behavioral tests that embrace abundant motor and non-motor performance in a unique mutant mouse model which correspond to the varied symptoms observed in human PD. The aim of this study is to evaluate the responsibility of the unique reduction of dopamine in the varied motor and non-motor symptoms of PD via a transgenic mice model. We analyzed neurotransmitter concentrations in the brain tissue of 18-month-old mutant mice, with selective inactivation of one allele of Vmat2 in dopaminergic neurons (VMAT2DATcre-HET) to confirm the selective reduction of dopamine, and then examined behavioral functions. Neurochemical tests showed lower dopamine concentrations in specific brain regions of VMAT2DATcre-HET mice, especially the ventral tegmental area/substantia nigra and striatum, together with relatively unchanging concentrations of norepinephrine and serotonin, demonstrating the dopaminergic specificity of this mouse model. Behavioral tasks showed impairments in several motor functions and major defects in olfactory abilities in the VMAT2DATcre-HET mice. However, no significant changes were found in the majority of non-motor tests, such as emotional performance and sleep patterns. We concluded from this study that the selective inactivation of one allele of the Vmat2 gene in dopaminergic neurons was related to dopamine reduction, resulting in phenotypes resembling some of the major deficits in PD, especially those of motor symptoms and olfactory functions.
Highlights
Parkinson’s disease (PD) is a common and complicated neurodegenerative disease with motor deficits, including static tremor, rigidity, bradykinesia, and non-motor dysfunctions, such as hyposmia, sleep disturbance, and emotional disorders (Khoo et al, 2013; Kalia and Lang, 2015)
We focused on heterozygous (HET) Vesicular monoamine transporter 2 (VMAT2)-deficient (VMAT2DATcre-HET) mice that exhibit a 50% reduction in Vmat2 expression in dopaminergic neurons, and behavioral tasks were used to determine which motor and/or non-motor symptoms related to PD were observed in this mouse model
Compared with the values observed in WT mice, the VMAT2DATcre-HET mice showed an ∼50% reduction of dopamine in the ventral tegmental area/substantia nigra (VTA/SN) (WT, 1.641 ± 0.300 pmol/mg; HET, 0.868 ± 0.146 pmol/mg; p = 0.049; Figure 1A), raphe (WT, 0.681 ± 0.070 pmol/mg; HET, FIGURE 1 | Compared to the WT mice (WT), the VMAT2DATcre-HET mice (HET) showed alterations of monoamine concentrations in different brain regions, with the specific reduction of dopamine concentration in the VTA/SN, raphe and hippocampus (A), and in the nucleus accumbens (NAC) and striatum (B)
Summary
Parkinson’s disease (PD) is a common and complicated neurodegenerative disease with motor deficits, including static tremor, rigidity, bradykinesia, and non-motor dysfunctions, such as hyposmia, sleep disturbance, and emotional disorders (Khoo et al, 2013; Kalia and Lang, 2015). Vesicular monoamine transporter 2, encoded by the gene SLC18A2, is a subtype of VMAT that is located in the central nervous system (Eiden et al, 2004; Lawal and Krantz, 2013) and is responsible for packaging and transporting monoamines (dopamine, norepinephrine, and serotonin) in small synaptic vesicles in monoaminergic neurons (Bernstein et al, 2014; Lohr et al, 2017). Among all these neurotransmitters, it is generally accepted in the scientific community that dopamine is closely involved in the pathophysiology of PD. It has been deduced that VMAT2 dysfunction can lead to a reduction of dopamine in vesicles and further intracellular accumulation of dopamine-generated toxic products, resulting in the degeneration of dopaminergic neurons, in the striatum, which is responsible for PD symptoms (Olanow and Tatton, 1999; Pifl et al, 2014)
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