White matter abnormalities in the Hdc knockout mouse, a model of tic and OCD pathophysiology
IntroductionAn inactivating mutation in the histidine decarboxylase gene (Hdc) has been identified as a rare but high-penetrance genetic cause of Tourette syndrome (TS). TS is a neurodevelopmental syndrome characterized by recurrent motor and vocal tics; it is accompanied by structural and functiona...
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2022.1037481/full |
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| author | Kantiya Jindachomthong Chengran Yang Yuegao Huang Daniel Coman Maximiliano Rapanelli Fahmeed Hyder Fahmeed Hyder Joseph Dougherty Luciana Frick Christopher Pittenger Christopher Pittenger Christopher Pittenger Christopher Pittenger |
| author_facet | Kantiya Jindachomthong Chengran Yang Yuegao Huang Daniel Coman Maximiliano Rapanelli Fahmeed Hyder Fahmeed Hyder Joseph Dougherty Luciana Frick Christopher Pittenger Christopher Pittenger Christopher Pittenger Christopher Pittenger |
| author_sort | Kantiya Jindachomthong |
| collection | DOAJ |
| description | IntroductionAn inactivating mutation in the histidine decarboxylase gene (Hdc) has been identified as a rare but high-penetrance genetic cause of Tourette syndrome (TS). TS is a neurodevelopmental syndrome characterized by recurrent motor and vocal tics; it is accompanied by structural and functional abnormalities in the cortico-basal ganglia circuitry. Hdc, which is expressed both in the posterior hypothalamus and peripherally, encodes an enzyme required for the biosynthesis of histamine. Hdc knockout mice (Hdc-KO) functionally recapitulate this mutation and exhibit behavioral and neurochemical abnormalities that parallel those seen in patients with TS.Materials and methodsWe performed exploratory RNA-seq to identify pathological alterations in several brain regions in Hdc-KO mice. Findings were corroborated with RNA and protein quantification, immunohistochemistry, and ex vivo brain imaging using MRI.ResultsExploratory RNA-Seq analysis revealed, unexpectedly, that genes associated with oligodendrocytes and with myelin production are upregulated in the dorsal striatum of these mice. This was confirmed by qPCR, immunostaining, and immunoblotting. These results suggest an abnormality in myelination in the striatum. To test this in an intact mouse brain, we performed whole-brain ex vivo diffusion tensor imaging (DTI), which revealed reduced fractional anisotropy (FA) in the dorsal striatum.DiscussionWhile the DTI literature in individuals with TS is sparse, these results are consistent with findings of disrupted descending cortical projections in patients with tics. The Hdc-KO model may represent a powerful system in which to examine the developmental mechanisms underlying this abnormality. |
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| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-04-13T08:21:34Z |
| publishDate | 2022-11-01 |
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| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-b60bdfca7d2f472aac3c5f04aa3ce3f52022-12-22T02:54:39ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992022-11-011510.3389/fnmol.2022.10374811037481White matter abnormalities in the Hdc knockout mouse, a model of tic and OCD pathophysiologyKantiya Jindachomthong0Chengran Yang1Yuegao Huang2Daniel Coman3Maximiliano Rapanelli4Fahmeed Hyder5Fahmeed Hyder6Joseph Dougherty7Luciana Frick8Christopher Pittenger9Christopher Pittenger10Christopher Pittenger11Christopher Pittenger12Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United StatesDepartment of Genetics, Washington University in St. Louis, St. Louis, MO, United StatesDepartment of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, United StatesDepartment of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, United StatesDepartment of Psychiatry, Yale University School of Medicine, New Haven, CT, United StatesDepartment of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, United StatesDepartment of Biomedical Engineering, Yale University School of Medicine, New Haven, CT, United StatesDepartment of Genetics, Washington University in St. Louis, St. Louis, MO, United StatesDepartment of Psychiatry, Yale University School of Medicine, New Haven, CT, United StatesDepartment of Psychiatry, Yale University School of Medicine, New Haven, CT, United StatesYale Child Study Center, Yale University School of Medicine, New Haven, CT, United StatesInterdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, CT, United StatesCenter for Brain and Mind Health, Yale University School of Medicine, New Haven, CT, United StatesIntroductionAn inactivating mutation in the histidine decarboxylase gene (Hdc) has been identified as a rare but high-penetrance genetic cause of Tourette syndrome (TS). TS is a neurodevelopmental syndrome characterized by recurrent motor and vocal tics; it is accompanied by structural and functional abnormalities in the cortico-basal ganglia circuitry. Hdc, which is expressed both in the posterior hypothalamus and peripherally, encodes an enzyme required for the biosynthesis of histamine. Hdc knockout mice (Hdc-KO) functionally recapitulate this mutation and exhibit behavioral and neurochemical abnormalities that parallel those seen in patients with TS.Materials and methodsWe performed exploratory RNA-seq to identify pathological alterations in several brain regions in Hdc-KO mice. Findings were corroborated with RNA and protein quantification, immunohistochemistry, and ex vivo brain imaging using MRI.ResultsExploratory RNA-Seq analysis revealed, unexpectedly, that genes associated with oligodendrocytes and with myelin production are upregulated in the dorsal striatum of these mice. This was confirmed by qPCR, immunostaining, and immunoblotting. These results suggest an abnormality in myelination in the striatum. To test this in an intact mouse brain, we performed whole-brain ex vivo diffusion tensor imaging (DTI), which revealed reduced fractional anisotropy (FA) in the dorsal striatum.DiscussionWhile the DTI literature in individuals with TS is sparse, these results are consistent with findings of disrupted descending cortical projections in patients with tics. The Hdc-KO model may represent a powerful system in which to examine the developmental mechanisms underlying this abnormality.https://www.frontiersin.org/articles/10.3389/fnmol.2022.1037481/fullanimal modeltourette syndromehistaminemyelinstriatum |
| spellingShingle | Kantiya Jindachomthong Chengran Yang Yuegao Huang Daniel Coman Maximiliano Rapanelli Fahmeed Hyder Fahmeed Hyder Joseph Dougherty Luciana Frick Christopher Pittenger Christopher Pittenger Christopher Pittenger Christopher Pittenger White matter abnormalities in the Hdc knockout mouse, a model of tic and OCD pathophysiology Frontiers in Molecular Neuroscience animal model tourette syndrome histamine myelin striatum |
| title | White matter abnormalities in the Hdc knockout mouse, a model of tic and OCD pathophysiology |
| title_full | White matter abnormalities in the Hdc knockout mouse, a model of tic and OCD pathophysiology |
| title_fullStr | White matter abnormalities in the Hdc knockout mouse, a model of tic and OCD pathophysiology |
| title_full_unstemmed | White matter abnormalities in the Hdc knockout mouse, a model of tic and OCD pathophysiology |
| title_short | White matter abnormalities in the Hdc knockout mouse, a model of tic and OCD pathophysiology |
| title_sort | white matter abnormalities in the hdc knockout mouse a model of tic and ocd pathophysiology |
| topic | animal model tourette syndrome histamine myelin striatum |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2022.1037481/full |
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