Mirte Scheper, Frederik N. F. Sørensen, Gabriele Ruffolo, Alessandro Gaeta, Lilian J. Lissner, Jasper J. Anink, Irina Korshunova, Floor E. Jansen, Kate Riney, Wim van Hecke, Angelika Mühlebner, Konstantin Khodosevich, Dirk Schubert, Eleonora Palma, James D. Mills, Eleonora Aronica
{"title":"结节性硬化症复合体内侧神经节突起神经元的 GABA 能调节受损和发育不成熟","authors":"Mirte Scheper, Frederik N. F. Sørensen, Gabriele Ruffolo, Alessandro Gaeta, Lilian J. Lissner, Jasper J. Anink, Irina Korshunova, Floor E. Jansen, Kate Riney, Wim van Hecke, Angelika Mühlebner, Konstantin Khodosevich, Dirk Schubert, Eleonora Palma, James D. Mills, Eleonora Aronica","doi":"10.1007/s00401-024-02737-7","DOIUrl":null,"url":null,"abstract":"<div><p>GABAergic interneurons play a critical role in maintaining neural circuit balance, excitation–inhibition regulation, and cognitive function modulation. In tuberous sclerosis complex (TSC), GABAergic neuron dysfunction contributes to disrupted network activity and associated neurological symptoms, assumingly in a cell type-specific manner. This GABAergic centric study focuses on identifying specific interneuron subpopulations within TSC, emphasizing the unique characteristics of medial ganglionic eminence (MGE)- and caudal ganglionic eminence (CGE)-derived interneurons. Using single-nuclei RNA sequencing in TSC patient material, we identify somatostatin-expressing (SST+) interneurons as a unique and immature subpopulation in TSC. The disrupted maturation of SST+ interneurons may undergo an incomplete switch from excitatory to inhibitory GABAergic signaling during development, resulting in reduced inhibitory properties. Notably, this study reveals markers of immaturity specifically in SST+ interneurons, including an abnormal <i>NKCC1/KCC2</i> ratio, indicating an imbalance in chloride homeostasis crucial for the postsynaptic consequences of GABAergic signaling as well as the downregulation of GABA<sub>A</sub> receptor subunits, <i>GABRA1</i>, and upregulation of <i>GABRA2.</i> Further exploration of SST+ interneurons revealed altered localization patterns of SST+ interneurons in TSC brain tissue, concentrated in deeper cortical layers, possibly linked to cortical dyslamination. In the epilepsy context, our research underscores the diverse cell type-specific roles of GABAergic interneurons in shaping seizures, advocating for precise therapeutic considerations. Moreover, this study illuminates the potential contribution of SST+ interneurons to TSC pathophysiology, offering insights for targeted therapeutic interventions.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3000,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02737-7.pdf","citationCount":"0","resultStr":"{\"title\":\"Impaired GABAergic regulation and developmental immaturity in interneurons derived from the medial ganglionic eminence in the tuberous sclerosis complex\",\"authors\":\"Mirte Scheper, Frederik N. F. Sørensen, Gabriele Ruffolo, Alessandro Gaeta, Lilian J. Lissner, Jasper J. Anink, Irina Korshunova, Floor E. Jansen, Kate Riney, Wim van Hecke, Angelika Mühlebner, Konstantin Khodosevich, Dirk Schubert, Eleonora Palma, James D. Mills, Eleonora Aronica\",\"doi\":\"10.1007/s00401-024-02737-7\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>GABAergic interneurons play a critical role in maintaining neural circuit balance, excitation–inhibition regulation, and cognitive function modulation. In tuberous sclerosis complex (TSC), GABAergic neuron dysfunction contributes to disrupted network activity and associated neurological symptoms, assumingly in a cell type-specific manner. This GABAergic centric study focuses on identifying specific interneuron subpopulations within TSC, emphasizing the unique characteristics of medial ganglionic eminence (MGE)- and caudal ganglionic eminence (CGE)-derived interneurons. Using single-nuclei RNA sequencing in TSC patient material, we identify somatostatin-expressing (SST+) interneurons as a unique and immature subpopulation in TSC. The disrupted maturation of SST+ interneurons may undergo an incomplete switch from excitatory to inhibitory GABAergic signaling during development, resulting in reduced inhibitory properties. Notably, this study reveals markers of immaturity specifically in SST+ interneurons, including an abnormal <i>NKCC1/KCC2</i> ratio, indicating an imbalance in chloride homeostasis crucial for the postsynaptic consequences of GABAergic signaling as well as the downregulation of GABA<sub>A</sub> receptor subunits, <i>GABRA1</i>, and upregulation of <i>GABRA2.</i> Further exploration of SST+ interneurons revealed altered localization patterns of SST+ interneurons in TSC brain tissue, concentrated in deeper cortical layers, possibly linked to cortical dyslamination. In the epilepsy context, our research underscores the diverse cell type-specific roles of GABAergic interneurons in shaping seizures, advocating for precise therapeutic considerations. Moreover, this study illuminates the potential contribution of SST+ interneurons to TSC pathophysiology, offering insights for targeted therapeutic interventions.</p></div>\",\"PeriodicalId\":7012,\"journal\":{\"name\":\"Acta Neuropathologica\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":9.3000,\"publicationDate\":\"2024-05-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://link.springer.com/content/pdf/10.1007/s00401-024-02737-7.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Acta Neuropathologica\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://link.springer.com/article/10.1007/s00401-024-02737-7\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta Neuropathologica","FirstCategoryId":"3","ListUrlMain":"https://link.springer.com/article/10.1007/s00401-024-02737-7","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Impaired GABAergic regulation and developmental immaturity in interneurons derived from the medial ganglionic eminence in the tuberous sclerosis complex
GABAergic interneurons play a critical role in maintaining neural circuit balance, excitation–inhibition regulation, and cognitive function modulation. In tuberous sclerosis complex (TSC), GABAergic neuron dysfunction contributes to disrupted network activity and associated neurological symptoms, assumingly in a cell type-specific manner. This GABAergic centric study focuses on identifying specific interneuron subpopulations within TSC, emphasizing the unique characteristics of medial ganglionic eminence (MGE)- and caudal ganglionic eminence (CGE)-derived interneurons. Using single-nuclei RNA sequencing in TSC patient material, we identify somatostatin-expressing (SST+) interneurons as a unique and immature subpopulation in TSC. The disrupted maturation of SST+ interneurons may undergo an incomplete switch from excitatory to inhibitory GABAergic signaling during development, resulting in reduced inhibitory properties. Notably, this study reveals markers of immaturity specifically in SST+ interneurons, including an abnormal NKCC1/KCC2 ratio, indicating an imbalance in chloride homeostasis crucial for the postsynaptic consequences of GABAergic signaling as well as the downregulation of GABAA receptor subunits, GABRA1, and upregulation of GABRA2. Further exploration of SST+ interneurons revealed altered localization patterns of SST+ interneurons in TSC brain tissue, concentrated in deeper cortical layers, possibly linked to cortical dyslamination. In the epilepsy context, our research underscores the diverse cell type-specific roles of GABAergic interneurons in shaping seizures, advocating for precise therapeutic considerations. Moreover, this study illuminates the potential contribution of SST+ interneurons to TSC pathophysiology, offering insights for targeted therapeutic interventions.
期刊介绍:
Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.