Developmental deficits of MGE-derived interneurons in the Cntnap2 knockout mouse model of autism spectrum disorder
Interneurons are fundamental cells for maintaining the excitation-inhibition balance in the brain in health and disease. While interneurons have been shown to play a key role in the pathophysiology of autism spectrum disorder (ASD) in adult mice, little is known about how their maturation is altered...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-02-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2023.1112062/full |
| _version_ | 1797937339460222976 |
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| author | Noorya Yasmin Ahmed Rhys Knowles Lixinyu Liu Yiming Yan Xiaohan Li Ulrike Schumann Yumeng Wang Yovina Sontani Nathan Reynolds Riccardo Natoli Jiayu Wen Isabel Del Pino Da Mi Nathalie Dehorter |
| author_facet | Noorya Yasmin Ahmed Rhys Knowles Lixinyu Liu Yiming Yan Xiaohan Li Ulrike Schumann Yumeng Wang Yovina Sontani Nathan Reynolds Riccardo Natoli Jiayu Wen Isabel Del Pino Da Mi Nathalie Dehorter |
| author_sort | Noorya Yasmin Ahmed |
| collection | DOAJ |
| description | Interneurons are fundamental cells for maintaining the excitation-inhibition balance in the brain in health and disease. While interneurons have been shown to play a key role in the pathophysiology of autism spectrum disorder (ASD) in adult mice, little is known about how their maturation is altered in the developing striatum in ASD. Here, we aimed to track striatal developing interneurons and elucidate the molecular and physiological alterations in the Cntnap2 knockout mouse model. Using Stereo-seq and single-cell RNA sequencing data, we first characterized the pattern of expression of Cntnap2 in the adult brain and at embryonic stages in the medial ganglionic eminence (MGE), a transitory structure producing most cortical and striatal interneurons. We found that Cntnap2 is enriched in the striatum, compared to the cortex, particularly in the developing striatal cholinergic interneurons. We then revealed enhanced MGE-derived cell proliferation, followed by increased cell loss during the canonical window of developmental cell death in the Cntnap2 knockout mice. We uncovered specific cellular and molecular alterations in the developing Lhx6-expressing cholinergic interneurons of the striatum, which impacts interneuron firing properties during the first postnatal week. Overall, our work unveils some of the mechanisms underlying the shift in the developmental trajectory of striatal interneurons which greatly contribute to the ASD pathogenesis. |
| first_indexed | 2024-04-10T18:43:04Z |
| format | Article |
| id | doaj.art-a02577ef8e674f5ab20f5224e83bb859 |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-04-10T18:43:04Z |
| publishDate | 2023-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-a02577ef8e674f5ab20f5224e83bb8592023-02-01T11:26:35ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2023-02-011110.3389/fcell.2023.11120621112062Developmental deficits of MGE-derived interneurons in the Cntnap2 knockout mouse model of autism spectrum disorderNoorya Yasmin Ahmed0Rhys Knowles1Lixinyu Liu2Yiming Yan3Xiaohan Li4Ulrike Schumann5Yumeng Wang6Yovina Sontani7Nathan Reynolds8Riccardo Natoli9Jiayu Wen10Isabel Del Pino11Da Mi12Nathalie Dehorter13The Australian National University, The John Curtin School of Medical Research, Canberra, ACT, AustraliaThe Australian National University, The John Curtin School of Medical Research, Canberra, ACT, AustraliaThe Australian National University, The John Curtin School of Medical Research, Canberra, ACT, AustraliaTsinghua-Peking Center for Life Sciences, IDG/McGovern Institute for Brain Research, School of Life Sciences, Tsinghua University, Beijing, ChinaTsinghua-Peking Center for Life Sciences, IDG/McGovern Institute for Brain Research, School of Life Sciences, Tsinghua University, Beijing, ChinaThe Australian National University, The John Curtin School of Medical Research, Canberra, ACT, AustraliaThe Australian National University, The John Curtin School of Medical Research, Canberra, ACT, AustraliaThe Australian National University, The John Curtin School of Medical Research, Canberra, ACT, AustraliaThe Australian National University, The John Curtin School of Medical Research, Canberra, ACT, AustraliaThe Australian National University, The John Curtin School of Medical Research, Canberra, ACT, AustraliaThe Australian National University, The John Curtin School of Medical Research, Canberra, ACT, AustraliaInstitute of Neurosciences, Spanish National Research Council (CSIC), Sant Joan d’Alacant, SpainTsinghua-Peking Center for Life Sciences, IDG/McGovern Institute for Brain Research, School of Life Sciences, Tsinghua University, Beijing, ChinaThe Australian National University, The John Curtin School of Medical Research, Canberra, ACT, AustraliaInterneurons are fundamental cells for maintaining the excitation-inhibition balance in the brain in health and disease. While interneurons have been shown to play a key role in the pathophysiology of autism spectrum disorder (ASD) in adult mice, little is known about how their maturation is altered in the developing striatum in ASD. Here, we aimed to track striatal developing interneurons and elucidate the molecular and physiological alterations in the Cntnap2 knockout mouse model. Using Stereo-seq and single-cell RNA sequencing data, we first characterized the pattern of expression of Cntnap2 in the adult brain and at embryonic stages in the medial ganglionic eminence (MGE), a transitory structure producing most cortical and striatal interneurons. We found that Cntnap2 is enriched in the striatum, compared to the cortex, particularly in the developing striatal cholinergic interneurons. We then revealed enhanced MGE-derived cell proliferation, followed by increased cell loss during the canonical window of developmental cell death in the Cntnap2 knockout mice. We uncovered specific cellular and molecular alterations in the developing Lhx6-expressing cholinergic interneurons of the striatum, which impacts interneuron firing properties during the first postnatal week. Overall, our work unveils some of the mechanisms underlying the shift in the developmental trajectory of striatal interneurons which greatly contribute to the ASD pathogenesis.https://www.frontiersin.org/articles/10.3389/fcell.2023.1112062/fullinterneuronmaturationstriatumautismCNTNAP2 |
| spellingShingle | Noorya Yasmin Ahmed Rhys Knowles Lixinyu Liu Yiming Yan Xiaohan Li Ulrike Schumann Yumeng Wang Yovina Sontani Nathan Reynolds Riccardo Natoli Jiayu Wen Isabel Del Pino Da Mi Nathalie Dehorter Developmental deficits of MGE-derived interneurons in the Cntnap2 knockout mouse model of autism spectrum disorder Frontiers in Cell and Developmental Biology interneuron maturation striatum autism CNTNAP2 |
| title | Developmental deficits of MGE-derived interneurons in the Cntnap2 knockout mouse model of autism spectrum disorder |
| title_full | Developmental deficits of MGE-derived interneurons in the Cntnap2 knockout mouse model of autism spectrum disorder |
| title_fullStr | Developmental deficits of MGE-derived interneurons in the Cntnap2 knockout mouse model of autism spectrum disorder |
| title_full_unstemmed | Developmental deficits of MGE-derived interneurons in the Cntnap2 knockout mouse model of autism spectrum disorder |
| title_short | Developmental deficits of MGE-derived interneurons in the Cntnap2 knockout mouse model of autism spectrum disorder |
| title_sort | developmental deficits of mge derived interneurons in the cntnap2 knockout mouse model of autism spectrum disorder |
| topic | interneuron maturation striatum autism CNTNAP2 |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2023.1112062/full |
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