The Ca2+-activated Cl- channel TMEM16B regulates action potential firing and axonal targeting in olfactory sensory neurons.
The Ca2+-activated Cl- channel TMEM16B regulates action potential firing and axonal targeting in olfactory sensory neurons.
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DOI：
10.1085/jgp.201611622
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发表时间：
2016-10
期刊：
影响因子：
--
通讯作者：
Boccaccio A
中科院分区：
文献类型：
--
作者：
Pietra G;Dibattista M;Menini A;Reisert J;Boccaccio A
TMEM16B在嗅觉感觉神经元中表达，但先前确定其在嗅觉中生理作用的尝试均未成功。皮耶特拉等人发现，TMEM16B基因敲除导致小鼠嗅觉行为以及嗅觉感觉神经元的细胞生理功能出现缺陷。
钙激活氯离子通道TMEM16B在嗅觉感觉神经元（OSNs）的纤毛中高度表达。尽管大部分气味诱发的转导电流由钙激活氯离子通道携带，但它们在嗅觉中的作用仍存在争议。先前的一份报告（比利格等人，2011年，《自然·神经科学》，http://dx.doi.org/10.1038/nn.2821）表明，小鼠中TMEM16b/Ano2基因的破坏消除了OSNs中的钙激活氯离子电流，但在嗅觉行为上没有产生任何重大变化。在此我们重新探讨TMEM16B在嗅觉中的作用，并表明TMEM16B基因敲除（KO）小鼠在气味引导的觅食能力方面存在行为缺陷。此外，由于TMEM16B在动作电位（AP）发放中的作用尚未被研究，我们使用电生理记录方法来测量OSNs的发放活动。从分离的嗅觉神经元进行的吸液电极记录以及从嗅上皮神经元的树突小结进行的细胞贴附式松散膜片记录表明，从TMEM16B基因敲除小鼠中随机选取的神经元对刺激的反应发放活动比野生型（WT）小鼠的更强。因为OSNs表达不同的气味受体（ORs），我们通过使用一种表达绿色荧光蛋白标记的I7受体的小鼠品系来限制变异性，已知该受体可被庚醛激活。在对庚醛的反应中，我们测量到与野生型相比，TMEM16B基因敲除小鼠中表达I7的神经元发放模式发生了显著变化：反应时间延长且动作电位数量增多。此外，TMEM16B的缺失导致表达I7的神经元基础发放活动显著降低，同时轴突靶向嗅球发生改变，导致出现多余的I7肾小球。因此，TMEM16B控制动作电位发放并确保表达I7的OSNs正确靶向肾小球。总之，这些结果表明TMEM16B在正常嗅觉中确实具有相关作用。
TMEM16B is expressed in olfactory sensory neurons, but previous attempts to establish a physiological role in olfaction have been unsuccessful. Pietra et al. find that genetic ablation of TMEM16B results in defects in the olfactory behavior of mice and the cellular physiology of olfactory sensory neurons. The Ca2+-activated Cl− channel TMEM16B is highly expressed in the cilia of olfactory sensory neurons (OSNs). Although a large portion of the odor-evoked transduction current is carried by Ca2+-activated Cl− channels, their role in olfaction is still controversial. A previous report (Billig et al. 2011. Nat. Neurosci. http://dx.doi.org/10.1038/nn.2821) showed that disruption of the TMEM16b/Ano2 gene in mice abolished Ca2+-activated Cl− currents in OSNs but did not produce any major change in olfactory behavior. Here we readdress the role of TMEM16B in olfaction and show that TMEM16B knockout (KO) mice have behavioral deficits in odor-guided food-finding ability. Moreover, as the role of TMEM16B in action potential (AP) firing has not yet been studied, we use electrophysiological recording methods to measure the firing activity of OSNs. Suction electrode recordings from isolated olfactory neurons and on-cell loose-patch recordings from dendritic knobs of neurons in the olfactory epithelium show that randomly selected neurons from TMEM16B KO mice respond to stimulation with increased firing activity than those from wild-type (WT) mice. Because OSNs express different odorant receptors (ORs), we restrict variability by using a mouse line that expresses a GFP-tagged I7 OR, which is known to be activated by heptanal. In response to heptanal, we measure dramatic changes in the firing pattern of I7-expressing neurons from TMEM16B KO mice compared with WT: responses are prolonged and display a higher number of APs. Moreover, lack of TMEM16B causes a markedly reduced basal spiking activity in I7-expressing neurons, together with an alteration of axonal targeting to the olfactory bulb, leading to the appearance of supernumerary I7 glomeruli. Thus, TMEM16B controls AP firing and ensures correct glomerular targeting of OSNs expressing I7. Altogether, these results show that TMEM16B does have a relevant role in normal olfaction.
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