Abstract：
OBJECTIVE: 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 MeCP2Tg1 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 MeCP2Tg1 mice and whether these morphological changes contribute to epilepsy susceptibility.
METHODS: 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 MeCP2Tg1 (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 MeCP2Tg1 (FVB):CaMKIIα-Cre (C57BL/6) mice or MeCP2Tg1:PV-Cre (C57BL/6) mice and their littermate controls to specifically label projection and PV+ neurons for structural analysis.
RESULTS: Epilepsy susceptibility was increased in MeCP2Tg1 mice. There was a reduced number of PV neurons and reduced dendritic complexity in the hippocampus of MeCP2Tg1 mice. The dendritic complexity in MeCP2Tg1 mice was increased compared to wild-type mice, and total dendritic spine density in dentate gyrus of MeCP2Tg1 mice was also increased. Total dendritic spine density was increased in CA1 of MeCP2Tg1 mice.
CONCLUSIONS: 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.
METHODS: 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 MeCP2Tg1 (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 MeCP2Tg1 (FVB):CaMKIIα-Cre (C57BL/6) mice or MeCP2Tg1:PV-Cre (C57BL/6) mice and their littermate controls to specifically label projection and PV+ neurons for structural analysis.
RESULTS: Epilepsy susceptibility was increased in MeCP2Tg1 mice. There was a reduced number of PV neurons and reduced dendritic complexity in the hippocampus of MeCP2Tg1 mice. The dendritic complexity in MeCP2Tg1 mice was increased compared to wild-type mice, and total dendritic spine density in dentate gyrus of MeCP2Tg1 mice was also increased. Total dendritic spine density was increased in CA1 of MeCP2Tg1 mice.
CONCLUSIONS: 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.
摘要：
目的：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，通常表现为癫痫和自闭症谱系障碍（ASD）合并症。转基因系MeCP2Tg1用于模拟MECP2重复综合征，并显示自闭症-癫痫并存。先前的工作表明，兴奋性/抑制性（E/I）失衡是癫痫和ASD的潜在共同机制。投射神经元和小白蛋白（PV）中间神经元占海马中E/I平衡的大部分。因此,我们探讨了MeCP2Tg1小鼠海马中投射和PV+神经元的结构变化是如何发生的,以及这些形态学变化是否有助于癫痫易感性.
方法：我们使用设计药物小鼠模型专门激活的中间神经元Designer受体来抑制海马中的抑制性神经元，以验证MeCP2Tg1的癫痫易感性（FVB，一种近交系，称为对Friend白血病病毒敏感）小鼠。记录脑电图以定义癫痫发作。我们在MeCP2Tg1（FVB）：CaMKIIα-Cre（C57BL/6）小鼠或MeCP2Tg1：PV-Cre（C57BL/6）小鼠及其同窝对照中进行了病毒的眼眶后注射，以特异性标记投射和PV神经元进行结构分析。
结果：MeCP2Tg1小鼠癫痫易感性增加。MeCP2Tg1小鼠海马中PV神经元数量减少，树突复杂性降低。与野生型小鼠相比，MeCP2Tg1小鼠的树突复杂性增加，MeCP2Tg1小鼠齿状回总树突棘密度也增加。MeCP2Tg1小鼠的CA1中总树突棘密度增加。
结论：MeCP2的过表达可能会破坏关键的信号通路，导致PV中间神经元的树突复杂性降低，投射神经元的树突脊柱密度增加。与MeCP2相关的兴奋性和抑制性神经元结构的这种相互调节暗示了其作为癫痫发展中的潜在靶标的重要性，并为自闭症和癫痫的共同发生提供了新的视角。
方法：我们使用设计药物小鼠模型专门激活的中间神经元Designer受体来抑制海马中的抑制性神经元，以验证MeCP2Tg1的癫痫易感性（FVB，一种近交系，称为对Friend白血病病毒敏感）小鼠。记录脑电图以定义癫痫发作。我们在MeCP2Tg1（FVB）：CaMKIIα-Cre（C57BL/6）小鼠或MeCP2Tg1：PV-Cre（C57BL/6）小鼠及其同窝对照中进行了病毒的眼眶后注射，以特异性标记投射和PV神经元进行结构分析。
结果：MeCP2Tg1小鼠癫痫易感性增加。MeCP2Tg1小鼠海马中PV神经元数量减少，树突复杂性降低。与野生型小鼠相比，MeCP2Tg1小鼠的树突复杂性增加，MeCP2Tg1小鼠齿状回总树突棘密度也增加。MeCP2Tg1小鼠的CA1中总树突棘密度增加。
结论：MeCP2的过表达可能会破坏关键的信号通路，导致PV中间神经元的树突复杂性降低，投射神经元的树突脊柱密度增加。与MeCP2相关的兴奋性和抑制性神经元结构的这种相互调节暗示了其作为癫痫发展中的潜在靶标的重要性，并为自闭症和癫痫的共同发生提供了新的视角。
