Cell-specific gain modulation by synaptically released zinc in cortical circuits of audition.
Cell-specific gain modulation by synaptically released zinc in cortical circuits of audition.
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DOI：
10.7554/elife.29893
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发表时间：
2017-09-09
期刊：
影响因子：
7.7
通讯作者：
Tzounopoulos T
中科院分区：
文献类型：
--
作者：
Anderson CT;Kumar M;Xiong S;Tzounopoulos T
在许多兴奋性突触中，移动的锌存在于谷氨酸能囊泡中，并与谷氨酸共同释放。离体研究证实，突触释放的（突触）锌抑制兴奋性神经传递在较低频率的突触活动，但增强稳态突触反应在较高频率的活动。然而，它仍然是未知的突触锌如何影响神经元的加工在体内。在这里，我们对清醒小鼠的初级听觉皮层的声音诱发神经元活动进行了成像。我们发现，突触锌增强了CaMKII表达的主神经元的声音诱发反应的增益，但它减少了小白蛋白和生长抑素表达的中间神经元的增益。这种调制是健全的强度依赖性，部分，NMDA受体的独立性。通过建立一个以前未知的突触锌和听觉皮层处理的增益控制之间的联系，我们的研究结果推进了解皮层突触机制，并创建一个新的框架，接近和解释听觉皮层在声音处理中的作用。许多人发现在忙碌的城市街道上很容易跟随对话，但这个看似简单的任务需要复杂的声音处理。大脑必须准确地区分语音和背景噪音，即使这些声音的音量和音高重叠。为了实现这一点，处理声音的神经元不断调整声音音量与其反应大小之间的关系。这有助于大脑更精确地区分不同的声音，但这是如何工作的仍然不清楚。锌离子是近3,000种不同的酶和调节蛋白的一部分，也有助于神经元在称为突触的连接处相互交流。在包括抑郁症和阿尔茨海默病在内的疾病中，已经看到突触处锌离子数量的变化。安德森和库马尔等人通过对小鼠大脑进行成像，发现锌离子会影响健康大脑处理声音的方式。用一种能暂时吸收锌离子的物质治疗小鼠，改变了神经元对不同音量声音的反应。这表明，锌离子引起兴奋性神经元，激活邻近细胞，增加他们对声音的反应。相反，锌离子会引起抑制性神经元，从而降低其他细胞的活性，降低它们对声音的反应。总体效果是改变大脑处理声音区域的兴奋性和抑制性活动的平衡。安德森、库马尔等人提出，当环境从安静到嘈杂，反之亦然时，这些变化使大脑更容易处理和区分不同的声音。除了揭示锌离子在正常听力中的作用外，这些发现还可以帮助我们了解耳鸣和听觉神经病等疾病（将信号从耳朵传递到大脑的神经受损，导致听力损失）。耳鸣和听觉神经病都涉及大脑增加或减少其对具有特定特征的声音的反应的能力的变化-这可能涉及锌离子的活性。
In many excitatory synapses, mobile zinc is found within glutamatergic vesicles and is coreleased with glutamate. Ex vivo studies established that synaptically released (synaptic) zinc inhibits excitatory neurotransmission at lower frequencies of synaptic activity but enhances steady state synaptic responses during higher frequencies of activity. However, it remains unknown how synaptic zinc affects neuronal processing in vivo. Here, we imaged the sound-evoked neuronal activity of the primary auditory cortex in awake mice. We discovered that synaptic zinc enhanced the gain of sound-evoked responses in CaMKII-expressing principal neurons, but it reduced the gain of parvalbumin- and somatostatin-expressing interneurons. This modulation was sound intensity-dependent and, in part, NMDA receptor-independent. By establishing a previously unknown link between synaptic zinc and gain control of auditory cortical processing, our findings advance understanding about cortical synaptic mechanisms and create a new framework for approaching and interpreting the role of the auditory cortex in sound processing. Many people find it easy to follow a conversation while on a busy city street, but this seemingly simple task requires sophisticated processing of sounds. The brain must accurately distinguish speech sounds from background noise, even though the volumes and pitches of those sounds overlap. To make this possible, neurons that process sounds continually adjust the relationship between the volume of a sound and the size of their response. This helps the brain to distinguish more precisely between different sounds, but how this works remains unclear. Zinc ions form part of almost 3,000 different enzymes and regulatory proteins, and also help neurons to communicate with one another at junctions called synapses. Changes to the amount of zinc ions at the synapses have been seen in disorders including depression and Alzheimer’s disease. By imaging the brains of mice, Anderson, Kumar et al. now show that zinc ions affect how the healthy brain processes sounds. Treating the mice with a substance that temporarily mops up zinc ions changed how neurons responded to sounds of different volumes. This revealed that zinc ions cause excitatory neurons, which activate neighboring cells, to increase their responses to sounds. Conversely, zinc ions cause inhibitory neurons, which reduce the activity of other cells, to decrease their responses to sounds. The overall effect is to change the balance of excitatory and inhibitory activity in areas of the brain that process sound. Anderson, Kumar et al. propose that these changes make it easier for the brain to process and distinguish different sounds as the environment changes from quiet to loud and vice versa. As well as revealing a role for zinc ions in normal hearing, these findings may help us to understand disorders such as tinnitus and auditory neuropathies (conditions where the nerve that carries signals from the ear to the brain is damaged, leading to hearing loss). Both tinnitus and auditory neuropathies involve changes in the brain’s ability to increase or decrease its responses to sounds with particular characteristics – processes that may involve the activity of zinc ions.