Xu Hong-Ping, Burbridge Timothy J, Chen Ming-Gang, Ge Xinxin, Zhang Yueyi, Zhou Zhimin Jimmy, Crair Michael C
Department of Neurobiology, Yale University, New Haven, CT, 06510.
Department of Ophthalmology and Visual Science, Yale University, New Haven, CT, 06510.
Dev Neurobiol. 2015 Jun;75(6):621-40. doi: 10.1002/dneu.22288. Epub 2015 Mar 30.
Spontaneous activity during early development is necessary for the formation of precise neural connections, but it remains uncertain whether activity plays an instructive or permissive role in brain wiring. In the visual system, retinal ganglion cell (RGC) projections to the brain form two prominent sensory maps, one reflecting eye of origin and the other retinotopic location. Recent studies provide compelling evidence supporting an instructive role for spontaneous retinal activity in the development of eye-specific projections, but evidence for a similarly instructive role in the development of retinotopy is more equivocal. Here, we report on experiments in which we knocked down the expression of β2-containing nicotinic acetylcholine receptors (β2-nAChRs) specifically in the retina through a Cre-loxP recombination strategy. Overall levels of spontaneous retinal activity in retina-specific β2-nAChR mutant mice (Rx-β2cKO), examined in vitro and in vivo, were reduced to a degree comparable to that observed in whole animal β2-nAChR mouse mutants (β2KO). However, many residual spontaneous waves in Rx-β2cKO mice displayed local propagating features with strong correlations between nearby but not distant RGCs typical of waves observed in wild-type (WT) but not β2KO mice. We further observed that eye-specific segregation was disrupted in Rx-β2cKO mice, but retinotopy was spared in a competition-dependent manner. These results suggest that propagating patterns of spontaneous retinal waves are essential for normal development of the retinotopic map, even while overall activity levels are significantly reduced, and support an instructive role for spontaneous retinal activity in both eye-specific segregation and retinotopic refinement.
早期发育过程中的自发活动对于精确神经连接的形成是必要的，但活动在大脑布线中是起指导性作用还是允许性作用仍不确定。在视觉系统中，视网膜神经节细胞（RGC）向大脑的投射形成两个突出的感觉图谱，一个反映起源眼，另一个反映视网膜拓扑位置。最近的研究提供了令人信服的证据，支持自发视网膜活动在眼特异性投射发育中起指导性作用，但在视网膜拓扑发育中类似指导性作用的证据则更具争议性。在这里，我们报告了通过Cre-loxP重组策略特异性敲低视网膜中含β2的烟碱型乙酰胆碱受体（β2-nAChRs）表达的实验。在体外和体内检测的视网膜特异性β2-nAChR突变小鼠（Rx-β2cKO）中，视网膜自发活动的总体水平降低到与全动物β2-nAChR小鼠突变体（β2KO）中观察到的程度相当。然而，Rx-β2cKO小鼠中的许多残留自发波表现出局部传播特征，附近但非远处的RGC之间具有很强的相关性，这是野生型（WT）而非β2KO小鼠中观察到的波的典型特征。我们进一步观察到，Rx-β2cKO小鼠的眼特异性分离受到破坏，但视网膜拓扑以竞争依赖的方式得以保留。这些结果表明，即使总体活动水平显著降低，自发视网膜波的传播模式对于视网膜拓扑图谱的正常发育也是必不可少的，并支持自发视网膜活动在眼特异性分离和视网膜拓扑细化中起指导性作用。
