Pregnancy-Associated Plasma Protein-aa Regulates Photoreceptor Synaptic Development to Mediate Visually Guided Behavior
Pregnancy-Associated Plasma Protein-aa Regulates Photoreceptor Synaptic Development to Mediate Visually Guided Behavior
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DOI：
10.1523/jneurosci.0061-18.2018
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发表时间：
2018-05-30
影响因子：
5.3
通讯作者：
Wolman, Marc A.
中科院分区：
文献类型：
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作者：
Miller, Andrew H.;Howe, Hollis B.;Wolman, Marc A.
为了指导行为，感觉系统检测刺激的开始和抵消，并通过平行通路处理这些不同的输入。在视网膜中，这种策略是通过将光感受器分别连接到ON和OFF双极细胞的突触来分裂光开始和抵消的神经信号来实现的。目前尚不清楚是哪些分子线索建立了这种突触结构的结构，以分裂光启动和光偏移信号。光感受器和一种双极细胞之间突触减少的突变体，可能会揭示一个关键的线索。通过这种方法，我们报道了妊娠相关血浆蛋白aa （pappaa）在促进传递光偏移信息的锥体突触的结构和功能方面的新突触作用。电生理和行为分析表明，pappaa突变斑马鱼具有锥体- off双极细胞突触功能障碍和对光偏移的反应受损，但锥体-on双极细胞突触和光起反应完整。pappaa突变体锥体的超微结构分析显示，与OFF双极细胞的突触缺乏突触前结构域。pappaa在视网膜突触形成过程中突触后向视锥细胞表达，并编码一种分泌的金属蛋白酶，这种蛋白酶可以刺激胰岛素样生长因子1 （IGF1）信号传导。在突触发生过程中，诱导显性负IGF1受体表达可减少光偏移反应。相反，此时刺激IGF1信号可以改善pappaa突变体的光偏移反应和锥体突触前结构。总之，我们的研究结果表明，pappaa调节的IGF1信号是一种新的途径，可以确定锥体突触如何传递光偏移信号来指导行为。
To guide behavior, sensory systems detect the onset and offset of stimuli and process these distinct inputs via parallel pathways. In the retina, this strategy is implemented by splitting neural signals for light onset and offset via synapses connecting photoreceptors to ON and OFF bipolar cells, respectively. It remains poorly understood which molecular cues establish the architecture of this synaptic configuration to split light-onset and light-offset signals. A mutant with reduced synapses between photoreceptors and one bipolar cell type, but not the other, could reveal a critical cue. From this approach, we report a novel synaptic role for pregnancy-associated plasma protein aa (pappaa) in promoting the structure and function of cone synapses that transmit light-offset information. Electrophysiological and behavioral analyses indicated pappaa mutant zebrafish have dysfunctional cone-to-OFF bipolar cell synapses and impaired responses to light offset, but intact cone-to-ON bipolar cell synapses and light-onset responses. Ultrastructural analyses of pappaa mutant cones showed a lack of presynaptic domains at synapses with OFF bipolar cells. pappaa is expressed postsynaptically to the cones during retinal synaptogenesis and encodes a secreted metalloprotease known to stimulate insulin-like growth factor 1 (IGF1) signaling. Induction of dominant-negative IGF1 receptor expression during synaptogenesis reduced light-offset responses. Conversely, stimulating IGF1 signaling at this time improved pappaa mutants' light-offset responses and cone presynaptic structures. Together, our results indicate Pappaa-regulated IGF1 signaling as a novel pathway that establishes how cone synapses convey light-offset signals to guide behavior.