Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China.
Jingzhou Hospital affiliated with Yangtze University, Jingzhou, China.
Epilepsia. 2024 Aug;65(8):2483-2496. doi: 10.1111/epi.18027. Epub 2024 May 31.
Methyl CpG-binding protein 2 (MECP2) duplication syndrome is a rare X-linked genomic disorder affecting predominantly males, which is usually manifested as epilepsy and autism spectrum disorder (ASD) comorbidity. The transgenic line MeCP2 was used for mimicking MECP2 duplication syndrome and showed autism-epilepsy co-occurrence. Previous works suggested that the excitatory/inhibitory (E/I) imbalance is a potential common mechanism for both epilepsy and ASD. The projection neurons and parvalbumin (PV) interneurons account for the majority of E/I balance in the hippocampus. Therefore, we explored how structural changes of projection and PV neurons occur in the hippocampus of MeCP2 mice and whether these morphological changes contribute to epilepsy susceptibility.
We used the interneuron Designer receptors exclusively activated by designer drugs mouse model to inhibit inhibitory neurons in the hippocampus to verify the epilepsy susceptibility of MeCP2 (FVB, an inbred strain named as sensitivity to Friend leukemia virus) mice. Electroencephalograms were recorded for the definition of seizure. We performed retro-orbital injection of virus in MeCP2 (FVB):CaMKIIα-Cre (C57BL/6) mice or MeCP2:PV-Cre (C57BL/6) mice and their littermate controls to specifically label projection and PV neurons for structural analysis.
Epilepsy susceptibility was increased in MeCP2 mice. There was a reduced number of PV neurons and reduced dendritic complexity in the hippocampus of MeCP2 mice. The dendritic complexity in MeCP2 mice was increased compared to wild-type mice, and total dendritic spine density in dentate gyrus of MeCP2 mice was also increased. Total dendritic spine density was increased in CA1 of MeCP2 mice.
Overexpression of MeCP2 may disrupt crucial signaling pathways, resulting in decreased dendritic complexity of PV interneurons and increased dendritic spine density of projection neurons. This reciprocal modulation of excitatory and inhibitory neuronal structures associated with MeCP2 implies its significance as a potential target in the development of epilepsy and offers a novel perspective on the co-occurrence of autism and epilepsy.
甲基 CpG 结合蛋白 2（MECP2）重复综合征是一种罕见的 X 连锁基因组疾病，主要影响男性，其通常表现为癫痫和自闭症谱系障碍（ASD）共病。转基因系 MeCP2 用于模拟 MECP2 重复综合征，并表现出自闭症-癫痫共病。先前的研究表明，兴奋性/抑制性（E/I）失衡是癫痫和 ASD 的潜在共同机制。投射神经元和钙结合蛋白 Parvalbumin（PV）中间神经元构成海马 E/I 平衡的主要部分。因此，我们探讨了 MeCP2 小鼠海马中投射和 PV 神经元的结构变化，以及这些形态变化是否导致癫痫易感性。
我们使用中间神经元 Designer 受体特异性激活 Designer 药物小鼠模型来抑制海马中的抑制性神经元，以验证 MeCP2（FVB，一种名为 Friend 白血病病毒易感性的近交系）小鼠的癫痫易感性。记录脑电图以定义癫痫发作。我们在 MeCP2（FVB）：CaMKIIα-Cre（C57BL/6）小鼠或 MeCP2：PV-Cre（C57BL/6）小鼠及其同窝对照小鼠中进行眶后注射病毒，以特异性标记投射和 PV 神经元进行结构分析。
MeCP2 小鼠的癫痫易感性增加。MeCP2 小鼠海马中的 PV 神经元数量减少，树突复杂性降低。与野生型小鼠相比，MeCP2 小鼠的树突复杂性增加，MeCP2 小鼠齿状回的总树突棘密度也增加。MeCP2 小鼠 CA1 区的总树突棘密度增加。
MeCP2 的过表达可能破坏关键信号通路，导致 PV 中间神经元树突复杂性降低和投射神经元树突棘密度增加。与 MeCP2 相关的兴奋性和抑制性神经元结构的这种相互调节表明其作为癫痫发生的潜在靶点的重要性，并为自闭症和癫痫共病提供了新的视角。
