Mouse models of Slc35a2 brain mosaicism reveal mechanisms of mild malformations of cortical development with oligodendroglial hyperplasia in epilepsy.

IF 6.6 1区 医学 Q1 CLINICAL NEUROLOGY
Epilepsia Pub Date : 2024-10-26 DOI:10.1111/epi.18166
Hyojung Yoon, Amanda Ringland, James J Anderson, Sahibjot Sran, Soad Elziny, Cindy Huynh, Noriyuki Shinagawa, Samantha Badertscher, Rachel R Corrigan, Lauren Mashburn-Warren, Foued Amari, Min Chen, Vincenzo Coppola, Peter B Crino, Tracy A Bedrosian
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引用次数: 0

Abstract

Objective: Brain somatic variants in SLC35A2 were recently identified as a genetic marker for mild malformations of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE). The role of SLC35A2 in cortical development and the contributions of abnormal neurons and oligodendrocytes to seizure activity in MOGHE remain largely unexplored.

Methods: Here, we generated a novel Slc35a2 floxed allele, which we used to develop two Slc35a2 conditional knockout mouse lines targeting (1) the Emx1 dorsal telencephalic lineage (excitatory neurons and glia) and (2) the Olig2 lineage (oligodendrocytes). We examined brain structure, behavior, and seizure activity.

Results: Knockout of Slc35a2 from the Emx1 lineage, which targets both cortical neurons and oligodendrocytes, resulted in early lethality and caused abnormal cortical development, increased oligodendroglial cell density, early onset seizures, and developmental delays akin to what is observed in patients with MOGHE. By tracing neuronal development with 5-Ethynyl-2'-deoxyuridine (EdU) birthdating experiments, we found that Slc35a2 deficiency disrupts corticogenesis by delaying radial migration of neurons from the subventricular zone. To discern the contributions of oligodendrocytes to these phenotypes, we knocked out Slc35a2 from the Olig2 lineage. This recapitulated the increased oligodendroglial cell density and resulted in abnormal electroencephalographic activity, but without a clear seizure phenotype, suggesting Slc35a2 deficiency in neurons is required for epileptogenesis.

Significance: This study presents two novel Slc35a2 conditional knockout mouse models and characterizes the effects on brain development, behavior, and epileptogenesis. Together, these results demonstrate a direct causal role for SLC35A2 in MOGHE-like phenotypes, including a critical role in neuronal migration during brain development, and identify neurons as key contributors to SLC35A2-related epileptogenesis.

Slc35a2 脑镶嵌小鼠模型揭示了癫痫患者皮质发育轻度畸形伴少突胶质细胞增生的机制。
目的:最近发现,SLC35A2的脑体细胞变异是轻度癫痫伴少突胶质细胞增生性皮质发育畸形(MOGHE)的遗传标记。SLC35A2在大脑皮层发育中的作用以及异常神经元和少突胶质细胞对MOGHE癫痫发作活动的贡献在很大程度上仍未得到探讨。我们研究了大脑结构、行为和癫痫发作活动:结果:Emx1系的Slc35a2靶向皮质神经元和少突胶质细胞,敲除Emx1系的Slc35a2会导致早期致死,并引起皮质发育异常、少突胶质细胞密度增加、早发癫痫发作和发育迟缓,这与在MOGHE患者中观察到的情况类似。通过用 5-乙炔基-2'-脱氧尿苷(EdU)催产实验追踪神经元的发育,我们发现 Slc35a2 缺乏会延迟神经元从室管膜下区的径向迁移,从而破坏皮质的形成。为了辨别少突胶质细胞对这些表型的贡献,我们敲除了 Olig2 系的 Slc35a2。这再现了少突胶质细胞密度的增加,并导致了异常的脑电活动,但没有明显的癫痫发作表型,表明神经元中 Slc35a2 的缺乏是癫痫发生所必需的:本研究提出了两种新型 Slc35a2 条件性基因敲除小鼠模型,并描述了它们对大脑发育、行为和癫痫发生的影响。这些结果共同证明了SLC35A2在MOGHE样表型中的直接因果作用,包括在大脑发育过程中神经元迁移中的关键作用,并确定神经元是SLC35A2相关癫痫发生的关键因素。
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来源期刊
Epilepsia
Epilepsia 医学-临床神经学
CiteScore
10.90
自引率
10.70%
发文量
319
审稿时长
2-4 weeks
期刊介绍: Epilepsia is the leading, authoritative source for innovative clinical and basic science research for all aspects of epilepsy and seizures. In addition, Epilepsia publishes critical reviews, opinion pieces, and guidelines that foster understanding and aim to improve the diagnosis and treatment of people with seizures and epilepsy.
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