PACAP-Deficient Mice Exhibit Light Parameter-Dependent Abnormalities on Nonvisual Photoreception and Early Activity Onset
PACAP-Deficient Mice Exhibit Light Parameter-Dependent Abnormalities on Nonvisual Photoreception and Early Activity Onset
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DOI：
10.1371/journal.pone.0009286
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发表时间：
2010-02-18
期刊：
影响因子：
3.7
通讯作者：
Baba, Akemichi
中科院分区：
文献类型：
--
作者：
Kawaguchi, Chihiro;Isojima, Yasushi;Baba, Akemichi
背景资料：已经提出，色素黑视蛋白在非视觉光感受中充当主导光感受器，包括生物钟的重置（夹带）、生命状态（活动、睡眠/觉醒周期等）的直接调谐或掩蔽，瞳孔对光反射（PLR）peptide腺苷酸环化酶激活多肽（PACAP）是专门与黑视素在视网膜神经节细胞的一个小的子集共表达，并预计将广泛参与这些反应，但是，在以前的报告中有不一致的，其功能作用还没有得到很好的理解。方法/主要发现：在这里，我们表明，PACAP缺陷小鼠表现出严重的功能障碍夹带在一个时间依赖性的方式。突变小鼠的异常是强度依赖性的相位延迟和持续时间依赖性的相位提前。敲除小鼠也表现出迟钝的掩蔽，这取决于光照条件，但并没有完全消失。通过输注PACAP-38恢复了突变小鼠的掩蔽功能障碍。相比之下，这些突变小鼠显示出正常的PLR。我们检查了突变小鼠的视网膜形态和神经支配，在黑视素免疫反应细胞中没有观察到明显的变化。这些数据表明，夹带和掩蔽的功能障碍是由PACAP的损失引起的，而不是由光输入本身的损失引起的。此外，PACAP缺陷小鼠表现出异常的早期活动，从黑暗期前约4小时开始，而不影响内源性生物钟的相位。结论/意义：尽管包括我们在内的一些小组报告了PACAP和PAC（1）基因敲除小鼠的光反应异常，但他们的结果不一致[1，2，3，4]。本文描述的PACAP基因敲除小鼠的光夹带功能的时间依赖性障碍可以整合以前报告中不一致的数据。通过在突变小鼠中输注PACAP-38恢复受损的掩蔽是PACAP和掩蔽之间关系的第一个直接证据。这些结果表明，PACAP调节特定的非视觉光反应，通过传递参数光信息，即强度和持续时间。本文最初报道的突变小鼠中的“早鸟”表型假设PACAP在日常行为模式中也起关键作用，特别是在光暗过渡期。
Background: The photopigment melanopsin has been suggested to act as a dominant photoreceptor in nonvisual photoreception including resetting of the circadian clock (entrainment), direct tuning or masking of vital status (activity, sleep/wake cycles, etc.), and the pupillary light reflex (PLR). Pituitary adenylate cyclase-activating polypeptide (PACAP) is exclusively coexpressed with melanopsin in a small subset of retinal ganglion cells and is predicted to be involved extensively in these responses; however, there were inconsistencies in the previous reports, and its functional role has not been well understood.Methodology/Principal Findings: Here we show that PACAP-deficient mice exhibited severe dysfunctions of entrainment in a time-dependent manner. The abnormalities in the mutant mice were intensity-dependent in phase delay and duration-dependent in phase advance. The knockout mice also displayed blunted masking, which was dependent on lighting conditions, but not completely lost. The dysfunctions of masking in the mutant mice were recovered by infusion of PACAP-38. By contrast, these mutant mice show a normal PLR. We examined the retinal morphology and innervations in the mutant mice, and no apparent changes were observed in melanopsin-immunoreactive cells. These data suggest that the dysfunctions of entrainment and masking were caused by the loss of PACAP, not by the loss of light input itself. Moreover, PACAP-deficient mice express an unusually early onset of activities, from approximately four hours before the dark period, without influencing the phase of the endogenous circadian clock.Conclusions/Significance: Although some groups including us reported the abnormalities in photic entrainments in PACAP-and PAC(1)-knockout mice, there were inconsistencies in their results [1,2,3,4]. The time-dependent dysfunctions of photic entrainment in the PACAP-knockout mice described in this paper can integrate the incompatible data in previous reports. The recovery of impaired masking by infusion of PACAP-38 in the mutant mice is the first direct evidence of the relationship between PACAP and masking. These results indicate that PACAP regulates particular nonvisual light responses by conveying parametric light information-that is, intensity and duration. The "early-bird'' phenotype in the mutant mice originally reported in this paper supposed that PACAP also has a critical role in daily behavioral patterns, especially during the light-to-dark transition period.