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 GABA_A 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.

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中发挥着关键作用。在结节性硬化症 (TSC) 中，GABA 能神经元功能障碍会导致网络活动中断和相关的神经系统症状，推测是以细胞类型特异性的方式。这项以 GABAergic 为中心的研究重点是识别 TSC 内的特定中间神经元亚群，强调内侧神经节隆起 (MGE) 和尾侧神经节隆起 (CGE) 衍生的中间神经元的独特特征。通过对 TSC 患者材料进行单核 RNA 测序，我们将表达生长抑素（SST+）的中间神经元鉴定为 TSC 中独特且不成熟的亚群。 SST+ 中间神经元的成熟受到干扰，可能会在发育过程中从兴奋性 GABA 信号传导不完全转变为抑制性 GABA 信号，从而导致抑制特性降低。值得注意的是，这项研究揭示了 SST+ 中间神经元中的不成熟标志，包括异常的NKCC1/KCC2比率，表明氯离子稳态失衡对于 GABA 信号传导的突触后后果以及 GABA _A受体亚基GABRA1的下调和上调至关重要GABRA2的。对 SST+ 中间神经元的进一步探索揭示了 TSC 脑组织中 SST+ 中间神经元的定位模式发生改变，集中在更深的皮质层，可能与皮质层剥离有关。在癫痫方面，我们的研究强调了 GABA 能中间神经元在癫痫发作中的不同细胞类型特异性作用，倡导精确的治疗考虑。此外，这项研究阐明了 SST+ 中间神经元对 TSC 病理生理学的潜在贡献，为靶向治疗干预提供了见解。