Differential effect on myelination through abolition of activity-dependent synaptic vesicle release or reduction of overall electrical activity of selected cortical projections in the mouse
Differential effect on myelination through abolition of activity-dependent synaptic vesicle release or reduction of overall electrical activity of selected cortical projections in the mouse
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DOI：
10.1111/joa.12974
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发表时间：
2019-09-01
影响因子：
2.4
通讯作者：
Hoerder-Suabedissen, Anna
中科院分区：
文献类型：
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作者：
Korrell, Kim V.;Disser, Jolande;Hoerder-Suabedissen, Anna
在中枢神经系统中，少突胶质细胞对轴突的髓鞘化对于动作电位的快速、跳跃式传导至关重要。由于髓鞘形成是大脑发育和可塑性的中心，并且缺陷与几种神经疾病如多发性硬化症、重度抑郁症、双相情感障碍和精神分裂症有关，因此阐明调节髓鞘形成的潜在机制是重要的。已经提出了许多机制，少突胶质细胞和活跃的轴突之间的通信可以调节活动依赖性髓鞘形成的发生和维持。我们比较了两种模型的“沉默”层V和/或VI皮质投射神经元从早期阶段，通过Kir2.1表达，内向整流钾通道，通过在子宫内电穿孔引入胚胎天（E）13.5，或抑制调节囊泡释放通过Cre依赖性敲除突触体相关蛋白25 kDA（SNAP 25）。SNAP 25是可溶性N-乙基马来酰亚胺融合蛋白附着蛋白受体（SNARE）复合物的组分，其是钙依赖性调节囊泡从突触释放所需的。在Ntsr 1-Cre; Ai 14; Snap 25（fl/fl）小鼠的第VI层皮质投射神经元中，我们发现抑制调节的囊泡释放显著降低了髓鞘碱性蛋白（MBP，用作髓鞘形成的标记物）的量和出生后第14天（P）的有髓鞘投射的量，而不影响脑中髓鞘形成开始的初始时间（在P7/P8）。此外，整体少突胶质细胞成熟似乎受到影响。在Ntsr 1-Cre; Ai 14; Snap 25（fl/fl）胼胝体中也观察到Ranvier节（NoR）长度减少的强烈趋势。在P14时，在Rbp 4-Cre; Ai 14; Snap 25（fl/fl）胼胝体中观察到同样强烈的NoR长度减少趋势，并且在P18时脊髓背柱中的g比减少。然而，当比较Rbp 4-Cre; Ai 14; Snap 25（fl/fl）和对照脑时，在纹状体中未检测到MBP水平的可测量差异。相反，Kir2.1在子宫内电穿孔在E13.5并没有显着影响MBP的量或有髓胼胝体轴突的数量在P14，但显着降低测量胼胝体中的NoR长度。因此，似乎神经元的兴奋性可能潜在地执行髓鞘特性的调节功能，而受调节的囊泡释放具有对总体髓鞘形成具有更显著影响的潜力，但以细胞类型特异性方式。
Myelination of axons by oligodendrocytes in the central nervous system is crucial for fast, saltatory conduction of action potentials. As myelination is central for brain development and plasticity, and deficits are implicated in several neural disorders such as multiple sclerosis, major depressive disorder, bipolar disorder and schizophrenia, it is important to elucidate the underlying mechanisms regulating myelination. Numerous mechanisms have been proposed by which the communication between oligodendrocytes and active axons may regulate the onset and maintenance of activity-dependent myelination. We compared two models of 'silencing' layer V and/or VI cortical projection neurons from early stages by either decreasing their excitability through Kir2.1 expression, an inward rectifying potassium channel, introduced through in utero electroporation at embryonic day (E)13.5, or inhibiting regulated vesicular release through Cre-dependent knock-out of synaptosomal associated protein 25 kDA (SNAP25). SNAP25 is a component of the soluble N-ethylmaleimide fusion protein attachment protein receptor (SNARE) complex, which, among others, is needed for calcium-dependent regulated vesicle release from synapses. In layer VI cortical projection neurons in the Ntsr1-Cre;Ai14;Snap25 (fl/fl) mouse, we found that inhibiting regulated vesicular release significantly decreased the amount of myelin basic protein (MBP, used as marker for myelination) and the amount of myelinated projections at postnatal day (P)14 without affecting the initial timing of onset of myelination in the brain (at P7/P8). Additionally, overall oligodendrocyte maturation appears to be affected. A strong trend towards reduced node of Ranvier (NoR) length was also observed in Ntsr1-Cre;Ai14;Snap25 (fl/fl) corpus callosum. An equally strong trend towards reduced NoR length was observed in Rbp4-Cre;Ai14;Snap25 (fl/fl) corpus callosum at P14, and the g-ratio in the spinal cord dorsal column was reduced at P18. However, no measurable differences in levels of MBP were detected in the striatum when comparing Rbp4-Cre;Ai14;Snap25 (fl/fl) and control brains. Conversely, Kir2.1 in utero electroporation at E13.5 did not significantly affect the amount of MBP or number of myelinated callosal axons at P14 but did significantly decrease the NoR length measured in the corpus callosum. It therefore seems likely that the excitability of the neuron can potentially perform a modulating function of myelin characteristics, whereas regulated vesicular release has the potential to have a more pronounced effect on overall myelination, but in a cell-type specific manner.