A Pitx3-deficient developmental mouse model for fine motor, olfactory, and gastrointestinal symptoms of Parkinson's disease
Parkinson's disease (PD) is characterized by the selective death of substantia nigra pars compacta (SNpc) dopaminergic neurons and includes both motor and non-motor symptoms. While numerous models exist for the study of typical PD motor deficits, fewer exist for non-motor symptoms. Previous stu...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-08-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996122001693 |
| _version_ | 1828805678139965440 |
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| author | Bin Song Jacob W. Feldmann Shibo Cao Melissa Feitosa Youngbin Kong Woori Kim Altana Schweitzer Pierre Leblanc Jeffrey S. Schweitzer Kwang-Soo Kim |
| author_facet | Bin Song Jacob W. Feldmann Shibo Cao Melissa Feitosa Youngbin Kong Woori Kim Altana Schweitzer Pierre Leblanc Jeffrey S. Schweitzer Kwang-Soo Kim |
| author_sort | Bin Song |
| collection | DOAJ |
| description | Parkinson's disease (PD) is characterized by the selective death of substantia nigra pars compacta (SNpc) dopaminergic neurons and includes both motor and non-motor symptoms. While numerous models exist for the study of typical PD motor deficits, fewer exist for non-motor symptoms. Previous studies have shown that a Pitx3−/− mouse model (aphakia or ak mouse) has specific developmental failure of the dopaminergic neuron population in the SNpc and that it can be used for the study of PD-related gross motor dysfunction as well as cognitive functional deficits. It remains unclear whether the aphakia mouse, both male and female, might also be used to model fine motor deficits and for additional studies of non-motor deficits associated with PD. Here, using an extensive battery of behavioral tests, we demonstrate that the aphakia mouse shows both gross and fine motor functional deficits compared with control mice. Furthermore, aphakia mice show deficits of olfactory function in buried pellet, odor discrimination and odor habituation/dishabituation tests. We also found that aphakia mice suffer from gastrointestinal dysfunction (e.g., longer whole gut transit time and colon motility deficits), suggesting that the mutation also affects function of the gut-brain axis in this animal model. Moreover, our data demonstrate that in the aphakia mouse, L-DOPA, the gold standard PD medication, can rescue both gross and fine motor function deficits but neither olfactory nor gastrointestinal symptoms, a pattern much like that seen in PD patients. Altogether, this suggests that the aphakia mouse is a suitable model for fine motor, olfactory and gastrointestinal behavioral studies of PD as well as for the development of novel disease-modifying therapeutics. Significance statement: While several animal models are available to study the major motor symptoms of PD, there are fewer that replicate non-motor symptoms, which constitute a major source of morbidity for patients. Moreover, available models often require manipulations resulting in sudden massive cell loss and inflammation, both of which may interfere with understanding of the direct effects of dopaminergic neuronal loss in the SNpc. We describe a model of congenital SNpc cell deficiency in a Pitx3−/− mouse and characterize it with a battery of behavioral tests suggesting that it closely mimics non-motor as well as motor symptoms of PD, providing a useful insight into the effects of the nigrostriatal dopamine deficit. Taken together, these data suggest that the ak mouse represents a useful model to study dopaminergic system function for both motor and non-motor symptoms of PD. |
| first_indexed | 2024-12-12T07:58:48Z |
| format | Article |
| id | doaj.art-c9f38490aafa408b85272d64db13705c |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-12T07:58:48Z |
| publishDate | 2022-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-c9f38490aafa408b85272d64db13705c2022-12-22T00:32:13ZengElsevierNeurobiology of Disease1095-953X2022-08-01170105777A Pitx3-deficient developmental mouse model for fine motor, olfactory, and gastrointestinal symptoms of Parkinson's diseaseBin Song0Jacob W. Feldmann1Shibo Cao2Melissa Feitosa3Youngbin Kong4Woori Kim5Altana Schweitzer6Pierre Leblanc7Jeffrey S. Schweitzer8Kwang-Soo Kim9Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA; Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA; Department of Neurosurgery, Huashan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China; Corresponding authors at: Department of Psychiatry and Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA.Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USADepartment of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA; Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USADepartment of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA; Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USADepartment of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA; Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USADepartment of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA; Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USADepartment of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA; Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USADepartment of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA; Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USADepartment of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USADepartment of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA; Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA; Corresponding authors at: Department of Psychiatry and Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA.Parkinson's disease (PD) is characterized by the selective death of substantia nigra pars compacta (SNpc) dopaminergic neurons and includes both motor and non-motor symptoms. While numerous models exist for the study of typical PD motor deficits, fewer exist for non-motor symptoms. Previous studies have shown that a Pitx3−/− mouse model (aphakia or ak mouse) has specific developmental failure of the dopaminergic neuron population in the SNpc and that it can be used for the study of PD-related gross motor dysfunction as well as cognitive functional deficits. It remains unclear whether the aphakia mouse, both male and female, might also be used to model fine motor deficits and for additional studies of non-motor deficits associated with PD. Here, using an extensive battery of behavioral tests, we demonstrate that the aphakia mouse shows both gross and fine motor functional deficits compared with control mice. Furthermore, aphakia mice show deficits of olfactory function in buried pellet, odor discrimination and odor habituation/dishabituation tests. We also found that aphakia mice suffer from gastrointestinal dysfunction (e.g., longer whole gut transit time and colon motility deficits), suggesting that the mutation also affects function of the gut-brain axis in this animal model. Moreover, our data demonstrate that in the aphakia mouse, L-DOPA, the gold standard PD medication, can rescue both gross and fine motor function deficits but neither olfactory nor gastrointestinal symptoms, a pattern much like that seen in PD patients. Altogether, this suggests that the aphakia mouse is a suitable model for fine motor, olfactory and gastrointestinal behavioral studies of PD as well as for the development of novel disease-modifying therapeutics. Significance statement: While several animal models are available to study the major motor symptoms of PD, there are fewer that replicate non-motor symptoms, which constitute a major source of morbidity for patients. Moreover, available models often require manipulations resulting in sudden massive cell loss and inflammation, both of which may interfere with understanding of the direct effects of dopaminergic neuronal loss in the SNpc. We describe a model of congenital SNpc cell deficiency in a Pitx3−/− mouse and characterize it with a battery of behavioral tests suggesting that it closely mimics non-motor as well as motor symptoms of PD, providing a useful insight into the effects of the nigrostriatal dopamine deficit. Taken together, these data suggest that the ak mouse represents a useful model to study dopaminergic system function for both motor and non-motor symptoms of PD.http://www.sciencedirect.com/science/article/pii/S0969996122001693Parkinson's diseasePitx3motor functionolfactory functiongastrointestinal functioninflammation |
| spellingShingle | Bin Song Jacob W. Feldmann Shibo Cao Melissa Feitosa Youngbin Kong Woori Kim Altana Schweitzer Pierre Leblanc Jeffrey S. Schweitzer Kwang-Soo Kim A Pitx3-deficient developmental mouse model for fine motor, olfactory, and gastrointestinal symptoms of Parkinson's disease Neurobiology of Disease Parkinson's disease Pitx3 motor function olfactory function gastrointestinal function inflammation |
| title | A Pitx3-deficient developmental mouse model for fine motor, olfactory, and gastrointestinal symptoms of Parkinson's disease |
| title_full | A Pitx3-deficient developmental mouse model for fine motor, olfactory, and gastrointestinal symptoms of Parkinson's disease |
| title_fullStr | A Pitx3-deficient developmental mouse model for fine motor, olfactory, and gastrointestinal symptoms of Parkinson's disease |
| title_full_unstemmed | A Pitx3-deficient developmental mouse model for fine motor, olfactory, and gastrointestinal symptoms of Parkinson's disease |
| title_short | A Pitx3-deficient developmental mouse model for fine motor, olfactory, and gastrointestinal symptoms of Parkinson's disease |
| title_sort | pitx3 deficient developmental mouse model for fine motor olfactory and gastrointestinal symptoms of parkinson s disease |
| topic | Parkinson's disease Pitx3 motor function olfactory function gastrointestinal function inflammation |
| url | http://www.sciencedirect.com/science/article/pii/S0969996122001693 |
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