Paul Jodi R, McKeown Alex S, Davis Jennifer A, Totsch Stacie K, Mintz Eric M, Kraft Timothy W, Cowell Rita M, Gamble Karen L
Departments of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
Department of Vision Sciences, University of Alabama at Birmingham, Birmingham, AL, USA.
Eur J Neurosci. 2017 Apr;45(8):1102-1110. doi: 10.1111/ejn.13549. Epub 2017 Mar 21.
Glycogen synthase kinase 3 (GSK3) is a serine-threonine kinase that regulates mammalian circadian rhythms at the behavioral, molecular and neurophysiological levels. In the central circadian pacemaker, the suprachiasmatic nucleus (SCN), inhibitory phosphorylation of GSK3 exhibits a rhythm across the 24 h day. We have recently shown that GSK3 is capable of influencing both the molecular clock and SCN neuronal activity rhythms. However, it is not known whether GSK3 regulates the response to environmental cues such as light. The goal of this study was to test the hypothesis that GSK3 activation mediates light-induced SCN excitability and photic entrainment. Immunofluorescence staining in the SCN of mice showed that late-night light exposure significantly increased GSK3 activity (decreased pGSK3β levels) 30-60 min after the light-pulse. In addition, pharmacological inhibition of GSK3 blocked the expected light-induced excitability in SCN neurons; however, this effect was not associated with changes in resting membrane potential or input resistance. Behaviorally, mice with constitutively active GSK3 (GSK3-KI) re-entrained to a 6-h phase advance in the light-dark cycle in significantly fewer days than WT control animals. Furthermore, the behavioral and SCN neuronal activity of GSK3-KI mice was phase-advanced compared to WT, in both normal and light-exposed conditions. Finally, GSK3-KI mice exhibited normal negative-masking behavior and electroretinographic responses to light, suggesting that the enhanced photic entrainment is not due to an overall increased sensitivity to light in these animals. Taken together, these results provide strong evidence that GSK3 activation contributes to light-induced phase-resetting at both the neurophysiological and behavioral levels.
糖原合酶激酶3（GSK3）是一种丝氨酸 - 苏氨酸激酶，在行为、分子和神经生理水平上调节哺乳动物的昼夜节律。在中枢昼夜节律起搏器视交叉上核（SCN）中，GSK3的抑制性磷酸化在24小时内呈现节律性变化。我们最近发现，GSK3能够影响分子时钟和SCN神经元活动节律。然而，尚不清楚GSK3是否调节对光等环境线索的反应。本研究的目的是检验GSK3激活介导光诱导的SCN兴奋性和光同步化这一假说。对小鼠SCN进行免疫荧光染色显示，深夜光照在光脉冲后30 - 60分钟显著增加了GSK3活性（降低了pGSK3β水平）。此外，GSK3的药理学抑制阻断了SCN神经元中预期的光诱导兴奋性；然而，这种效应与静息膜电位或输入电阻的变化无关。在行为方面，组成型激活GSK3的小鼠（GSK3 - KI）在明暗周期中重新同步到提前6小时的相位所需的天数明显少于野生型对照动物。此外，在正常和光照条件下，GSK3 - KI小鼠的行为和SCN神经元活动都比野生型提前。最后，GSK3 - KI小鼠表现出正常的负性掩蔽行为和对光的视网膜电图反应，这表明增强的光同步化不是由于这些动物对光的整体敏感性增加。综上所述，这些结果提供了强有力的证据，表明GSK3激活在神经生理和行为水平上都有助于光诱导的相位重置。
