Loss of kv3.1 tonotopicity and alterations in cAMP response element-binding protein signaling in central auditory neurons of hearing impaired mice
Loss of kv3.1 tonotopicity and alterations in cAMP response element-binding protein signaling in central auditory neurons of hearing impaired mice
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DOI：
10.1523/jneurosci.4554-03.2004
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发表时间：
2004-02-25
影响因子：
5.3
通讯作者：
Kaczmarek, LK
中科院分区：
文献类型：
--
作者：
von Hehn, CAA;Bhattacharjee, A;Kaczmarek, LK
kv3.1钾通道基因的启动子受Ca 2 +-cAMP反应元件调节，该元件结合转录因子cAMP反应元件结合蛋白（CREB）。Kv3.1在听觉脑干的斜方体内侧核（MNTB）内以音调梯度表达，其中Kv3.1水平在内侧端最高，这对应于高听觉频率。我们比较了Kv3.1，CREB和磷酸化形式的CREB（pCREB）在小鼠品系，保持良好的听力在整个生活中，CBA/J（CBA），一个遭受早期耳蜗毛细胞损失，C57 BL/6（BL/6）。在年轻（6周）和老年（8个月）CBA小鼠中检测到MNTB中Kv3.1免疫反应性的梯度。虽然没有检测到CREB的梯度，但pCREB免疫阳性细胞沿张力轴沿着聚集在不同的簇中。同样的模式Kv3.1，CREB，和pCREB的定位也发现在年轻的BL/6小鼠的时间（6周）时，听力是正常的。相反，在8个月时，当听力受损时，Kv3.1的梯度被取消。此外，在年老的BL/6小鼠中，CREB表达沿着张力轴减少，并且pCREB标记的模式似乎是随机的，沿沿着张力轴没有离散的pCREB阳性细胞簇。我们的研究结果是一致的假设，即听觉脑干神经元的持续活动是必要的Kv3.1 tonotopicity通过CREB通路的维护。
The promoter for the kv3.1 potassium channel gene is regulated by a Ca2+-cAMP responsive element, which binds the transcription factor cAMP response element-binding protein (CREB). Kv3.1 is expressed in a tonotopic gradient within the medial nucleus of the trapezoid body (MNTB) of the auditory brainstem, where Kv3.1 levels are highest at the medial end, which corresponds to high auditory frequencies. We have compared the levels of Kv3.1, CREB, and the phosphorylated form of CREB (pCREB) in a mouse strain that maintains good hearing throughout life, CBA/J (CBA), with one that suffers early cochlear hair cell loss, C57BL/6 (BL/6). A gradient of Kv3.1 immunoreactivity in the MNTB was detected in both young ( 6 week) and older ( 8 month) CBA mice. Although no gradient of CREB was detected, pCREB-immunopositive cells were grouped together in distinct clusters along the tonotopic axis. The same pattern of Kv3.1, CREB, and pCREB localization was also found in young BL/6 mice at a time ( 6 weeks) when hearing is normal. In contrast, at 8 months, when hearing is impaired, the gradient of Kv3.1 was abolished. Moreover, in the older BL/6 mice there was a decrease in CREB expression along the tonotopic axis, and the pattern of pCREB labeling appeared random, with no discrete clusters of pCREB-positive cells along the tonotopic axis. Our findings are consistent with the hypothesis that ongoing activity in auditory brainstem neurons is necessary for the maintenance of Kv3.1 tonotopicity through the CREB pathway.