Cepeda Carlos, Holley Sandra M, Barry Joshua, Oikonomou Katerina D, Yazon Vannah-Wila, Peng Allison, Argueta Deneen, Levine Michael S
bioRxiv. 2024 Oct 18:2024.10.15.618500. doi: 10.1101/2024.10.15.618500.
There is a growing consensus that brain development in Huntington's disease (HD) is abnormal, leading to the idea that HD is not only a neurodegenerative but also a neurodevelopmental disorder. Indeed, structural and functional abnormalities have been observed during brain development in both humans and animal models of HD. However, a concurrent study of cortical and striatal development in a genetic model of HD is still lacking. Here we report significant alterations of corticostriatal development in the R6/2 mouse model of juvenile HD. We examined wildtype (WT) and R6/2 mice at postnatal (P) days 7, 14, and 21. Morphological examination demonstrated early structural and cellular alterations reminiscent of malformations of cortical development, and electrophysiological recordings of cortical pyramidal neurons (CPNs) demonstrated significant age- and genotype-dependent changes of intrinsic membrane and synaptic properties. In general, R6/2 CPNs had reduced cell membrane capacitance and increased input resistance (P7 and P14), along with reduced frequency of spontaneous excitatory and inhibitory synaptic events during early development (P7), suggesting delayed cortical maturation. This was confirmed by increased occurrence of GABA receptor-mediated giant depolarizing potentials at P7. At P14, the rheobase of CPNs was significantly reduced, along with increased excitability. Altered membrane and synaptic properties of R6/2 CPNs recovered progressively, and by P21 they were similar to WT CPNs. In striatal medium-sized spiny neurons (MSNs), a different picture emerged. Intrinsic membrane properties were relatively normal throughout development, except for a transient increase in membrane capacitance at P14. The first alterations in MSNs synaptic activity were observed at P14 and consisted of significant deficits in GABAergic inputs, however, these also were normalized by P21. In contrast, excitatory inputs began to decrease at this age. We conclude that the developing HD brain is capable of compensating for early developmental abnormalities and that cortical alterations precede and are a main contributor of striatal changes. Addressing cortical maldevelopment could help prevent or delay disease manifestations.
人们越来越一致地认为，亨廷顿舞蹈病（HD）患者的大脑发育异常，这使得人们认为HD不仅是一种神经退行性疾病，也是一种神经发育障碍。事实上，在HD的人类和动物模型的大脑发育过程中都观察到了结构和功能异常。然而，目前仍缺乏对HD基因模型中皮质和纹状体发育的同步研究。在此，我们报告了青少年HD的R6/2小鼠模型中皮质纹状体发育的显著改变。我们在出生后（P）第7、14和21天检查了野生型（WT）和R6/2小鼠。形态学检查显示早期结构和细胞改变让人联想到皮质发育畸形，对皮质锥体神经元（CPN）的电生理记录显示内在膜和突触特性存在显著的年龄和基因型依赖性变化。一般来说，R6/2 CPN的细胞膜电容降低，输入电阻增加（P7和P14），同时在早期发育阶段（P7）自发兴奋性和抑制性突触事件的频率降低，这表明皮质成熟延迟。这在P7时GABA受体介导的巨大去极化电位发生率增加中得到证实。在P14时，CPN的基强度显著降低，兴奋性增加。R6/2 CPN改变的膜和突触特性逐渐恢复，到P21时它们与WT CPN相似。在纹状体中型多棘神经元（MSN）中，出现了不同的情况。在整个发育过程中，内在膜特性相对正常，除了在P14时膜电容短暂增加。MSN突触活动的首次改变在P14时观察到，表现为GABA能输入显著缺陷，然而，这些在P21时也恢复正常。相比之下，兴奋性输入在这个年龄开始减少。我们得出结论，发育中的HD大脑能够补偿早期发育异常，并且皮质改变先于纹状体改变并是纹状体变化的主要促成因素。解决皮质发育异常可能有助于预防或延缓疾病表现。
