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

IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY
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
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引用次数: 0

摘要

GABA 能中间神经元在维持神经回路平衡、兴奋-抑制调节和认知功能调节方面起着至关重要的作用。在结节性硬化症复合体(TSC)中,GABA能神经元功能障碍会导致网络活动紊乱和相关神经症状,这可能是一种细胞类型特异性方式。这项以GABA能神经元为中心的研究侧重于识别TSC中特定的中间神经元亚群,强调内侧神经节突起(MGE)和尾部神经节突起(CGE)衍生的中间神经元的独特性。通过对 TSC 患者材料进行单核 RNA 测序,我们发现表达体生长抑素(SST+)的中间神经元是 TSC 中一个独特的未成熟亚群。SST+中间神经元的成熟受到干扰,可能在发育过程中经历了从兴奋性到抑制性GABA能信号的不完全转换,从而导致抑制特性降低。值得注意的是,这项研究揭示了 SST+ 中间神经元的不成熟标记,包括异常的 NKCC1/KCC2 比率,表明对 GABA 能信号突触后后果至关重要的氯离子平衡失衡,以及 GABAA 受体亚基 GABRA1 的下调和 GABRA2 的上调。对SST+中间神经元的进一步研究发现,SST+中间神经元在TSC脑组织中的定位模式发生了改变,主要集中在较深的皮层,这可能与皮层分层障碍有关。在癫痫方面,我们的研究强调了GABA能中间神经元在形成癫痫发作中的不同细胞类型特异性作用,从而为精确治疗提供了依据。此外,这项研究还揭示了SST+中间神经元对TSC病理生理学的潜在贡献,为有针对性的治疗干预提供了启示。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Impaired GABAergic regulation and developmental immaturity in interneurons derived from the medial ganglionic eminence in the tuberous sclerosis complex

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.

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来源期刊
Acta Neuropathologica
Acta Neuropathologica 医学-病理学
CiteScore
23.70
自引率
3.90%
发文量
118
审稿时长
4-8 weeks
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.
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