Identification of Vulnerable Interneuron Subtypes in 15q13.3 Microdeletion Syndrome Using Single-Cell Transcriptomics
| Autor: | Carmelo Bellardita, Navneet A. Vasistha, Susmita Malwade, Konstantin Khodosevich, Matej Andelic, Borna Moric, Irina Korshunova, Janina Gasthaus, Ole Kiehn |
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| Rok vydání: | 2022 |
| Předmět: |
Chromosomes
Human Pair 15 biology Ganglionic eminence Interneuron Chromosome Disorders Microdeletion syndrome Cortex (botany) Transcriptome Mice medicine.anatomical_structure Neuroblast Interneurons Seizures Intellectual Disability biology.protein medicine Animals Copy-number variation Chromosome Deletion Neuroscience Biological Psychiatry Parvalbumin |
| Zdroj: | Malwade, S, Gasthaus, J, Bellardita, C, Andelic, M, Moric, B, Korshunova, I, Kiehn, O, Vasistha, N A & Khodosevich, K 2022, ' Identification of Vulnerable Interneuron Subtypes in 15q13.3 Microdeletion Syndrome Using Single-Cell Transcriptomics ', Biological Psychiatry, vol. 91, no. 8, pp. 727-739 . https://doi.org/10.1016/j.biopsych.2021.09.012 |
| ISSN: | 0006-3223 |
| DOI: | 10.1016/j.biopsych.2021.09.012 |
| Popis: | BACKGROUND: A number of rare copy number variants (CNVs) have been linked to neurodevelopmental disorders. However, because CNVs encompass many genes, it is often difficult to identify the mechanisms that lead to developmental perturbations.METHODS: We used 15q13.3 microdeletion to propose and validate a novel strategy to predict the impact of CNV genes on brain development that could further guide functional studies. We analyzed single-cell transcriptomics datasets containing cortical interneurons to identify their developmental vulnerability to 15q13.3 microdeletion, which was validated in mouse models.RESULTS: We found that Klf13-but not other 15q13.3 genes-is expressed by precursors and neuroblasts in the medial and caudal ganglionic eminences during development, with a peak of expression at embryonic day (E)13.5 and E18.5, respectively. In contrast, in the adult mouse brain, Klf13 expression is negligible. Using Df(h15q13.3)/+ and Klf13+/- embryos, we observed a precursor subtype-specific impairment in proliferation in the medial ganglionic eminence and caudal ganglionic eminence at E13.5 and E17.5, respectively, corresponding to vulnerability predicted by Klf13 expression patterns. Finally, Klf13+/- mice showed a layer-specific decrease in parvalbumin and somatostatin cortical interneurons accompanied by changes in locomotor and anxiety-related behavior.CONCLUSIONS: We show that the impact of 15q13.3 microdeletion on precursor proliferation is grounded in a reduction in Klf13 expression. The lack of Klf13 in Df(h15q13.3)/+ cortex might be the major reason for perturbed density of cortical interneurons. Thus, the behavioral defects seen in 15q13.3 microdeletion could stem from a developmental perturbation owing to selective vulnerability of cortical interneurons during sensitive stages of their development. |
| Databáze: | OpenAIRE |
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