Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
Dev Neurosci. 2022;44(6):671-677. doi: 10.1159/000525039. Epub 2022 May 17.
DEPDC5, the key gene within the mechanistic target of rapamycin (mTOR) pathway, is one of the most common causative genes in patients with epilepsy and malformation of cortical development (MCD). Although somatic mutations in the dorsal cortical progenitors generate the malformed cortex, its pathogenesis of hyperexcitability is complex and remains unclear. We specifically deleted Depdc5 in the mouse forebrain dorsal progenitors to model DEPDC5-related epilepsy and investigated whether and how parvalbumin interneurons were non-cell autonomously affected in the malformed cortex. We showed that long before seizures, coincident with microglia inflammation, proteolytic enzymes degraded perineuronal nets (PNNs) in the malformed cortex, resulting in parvalbumin (PV+) interneuron loss and presynaptic inhibition impairment. Our studies, therefore, uncovered the hitherto unknown role of PNN in mTOR-related MCD, providing a new framework for mechanistic-based therapeutic development.
DEPDC5 是雷帕霉素靶蛋白（mTOR）通路中的关键基因，是癫痫和皮质发育畸形（MCD）患者最常见的致病基因之一。虽然背侧皮质祖细胞的体细胞突变会产生畸形皮质，但其过度兴奋的发病机制很复杂，目前仍不清楚。我们专门在小鼠前脑背侧祖细胞中删除了 Depdc5，以模拟 DEPDC5 相关的癫痫，并研究了畸形皮质中的γ-氨基丁酸（γ-aminobutyric acid，GABA）能中间神经元是否以及如何受到非细胞自主的影响。我们发现，早在癫痫发作之前，与小胶质细胞炎症同时，蛋白水解酶降解了畸形皮质中的周围神经毡（perineuronal nets，PNNs），导致 GABA 能中间神经元（parvalbumin，PV+ interneuron）丢失和突触前抑制受损。因此，我们的研究揭示了 PNN 在 mTOR 相关 MCD 中的迄今未知的作用，为基于机制的治疗开发提供了新的框架。
