Impaired fast-spiking interneuron function in a genetic mouse model of depression.
Impaired fast-spiking interneuron function in a genetic mouse model of depression.
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DOI：
10.7554/elife.04979
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发表时间：
2015-03-03
期刊：
影响因子：
7.7
通讯作者：
Bartos M
中科院分区：
文献类型：
--
作者：
Sauer JF;Strüber M;Bartos M
有节奏的神经元活动为协同活动的细胞集合提供了信息编码的框架。异常的脑节律被认为是导致精神疾病的潜在病理生理机制，但潜在的网络缺陷在很大程度上是未知的。我们发现，表达截断的精神分裂症中断1 （Disc1）的小鼠，反映了人类精神疾病的高流行基因型，表现出抑郁相关的行为。在Disc1小鼠中，前边缘皮层（PrlC）的θ波和低伽马同步受损，并与行为绝望的程度呈负相关。虽然微弱的θ波活动是由海马驱动的，但低伽马振荡的干扰是由表达小白蛋白（PV）的快速峰值中间神经元（FS-INs）的局部缺陷引起的。FS-INs的数量减少，它们接受较少的兴奋性输入，并在靶标上形成较少的释放位点。计算分析表明，FS-INs的弱兴奋性输入和抑制性输出可能导致γ振荡受损。我们的数据链网络缺陷与人类抑郁症的基因突变有关。DOI: http://dx.doi.org/10.7554/eLife.04979.001我们的思想和情感是由大脑内复杂的神经元网络产生和处理的。信号通过化学信使从一个神经元传递到另一个神经元，并以电信号的形式在神经元之间传递。大脑某个区域产生的电信号通常表现出稳定的节奏或振荡。在许多被诊断患有某些精神疾病（如精神分裂症和重度抑郁症）的人的大脑中，这些振荡被破坏了，但这些节奏的变化是如何与电活动背后的神经元网络缺陷联系在一起的，目前还不太清楚。对苏格兰一个家庭几十年的研究表明，被诊断患有精神疾病的家庭成员的一个名为DISC1的基因缩短了。最近，科学家们已经能够创造出具有与这种DISC1突变相同突变的老鼠。希望通过研究这些突变小鼠的行为和神经活动，可以更好地理解人类的精神障碍。Sauer等人证实突变小鼠表现出抑郁相关行为；在试图逃离绝望境地的实验中，突变小鼠比正常小鼠更早地放弃了逃跑的尝试。这些“抑郁”老鼠的大脑活动记录显示，大脑边缘皮层的活动非常脆弱和紊乱，与人类抑郁症的大脑活动非常相似。特别是，两种类型的大脑活动，即θ波和低伽马波，没有同步。为了精确地确定是什么导致了这些异常的振荡，Sauer等人从抑郁的老鼠身上取下了大脑切片，然后用染料对它们进行染色，从而更清楚地显示出前边缘皮层的回路。结果表明，抑郁小鼠的一种特殊类型的抑制神经元——快速尖刺中间神经元——存在发育缺陷——这种细胞更少，而且那里的神经元与其他神经元之间的连接数量也不正确。进一步的研究表明，这些神经元难以接收和释放允许神经元交流的化学信使，Sauer等人认为这可能导致低伽马振荡问题。为了证实这一理论，Sauer等人创建了一个模拟有缺陷的中间神经元的计算机模型。模拟结果支持了一种理论，即快速脉冲中间神经元的缺陷导致了抑郁症小鼠中出现的异常的低伽马节律。在未来，更好地了解DISC1突变体和其他精神疾病小鼠模型中抑制细胞的缺陷可能为靶向药物设计开辟新的途径。由于前边缘皮层结合了来自其他大脑区域的输入，进一步的挑战将是检查这些输入是否会影响前边缘皮层的活动，从而导致与抑郁相关的行为。DOI: http://dx.doi.org/10.7554/eLife.04979.002
Rhythmic neuronal activity provides a frame for information coding by co-active cell assemblies. Abnormal brain rhythms are considered as potential pathophysiological mechanisms causing mental disease, but the underlying network defects are largely unknown. We find that mice expressing truncated Disrupted-in-Schizophrenia 1 (Disc1), which mirror a high-prevalence genotype for human psychiatric illness, show depression-related behavior. Theta and low-gamma synchrony in the prelimbic cortex (PrlC) is impaired in Disc1 mice and inversely correlated with the extent of behavioural despair. While weak theta activity is driven by the hippocampus, disturbance of low-gamma oscillations is caused by local defects of parvalbumin (PV)-expressing fast-spiking interneurons (FS-INs). The number of FS-INs is reduced, they receive fewer excitatory inputs, and form fewer release sites on targets. Computational analysis indicates that weak excitatory input and inhibitory output of FS-INs may lead to impaired gamma oscillations. Our data link network defects with a gene mutation underlying depression in humans. DOI: http://dx.doi.org/10.7554/eLife.04979.001 Our thoughts and emotions are produced and processed by complex networks of neurons inside our brains. Signals are sent from one neuron to another via chemical messengers, and pass through the neuron as an electrical signal. The electrical signals produced by a brain region often show steady rhythms, or oscillations. In the brains of many people diagnosed with certain mental disorders, such as schizophrenia and major depression, these oscillations are disrupted, but how these changes in rhythm are linked to defects in the networks of neurons behind the electrical activity is not well understood. Studies of a family in Scotland over several decades revealed that a gene called DISC1 was shortened in family members who had been diagnosed with mental illnesses. Recently, scientists have been able to create mice that have mutations that are equivalent to this DISC1 mutation. It is hoped that studying the behavior and neural activity of these mutant mice could lead to a better understanding of human mental disorders. Sauer et al. confirmed that the mutant mice showed depression-related behavior; in experiments that involved trying to escape from hopeless situations, the mutant mice gave up on their escape attempts much sooner than the normal mice. Recording the brain activity of these ‘depressed’ mice showed that the activity of a brain region called the prelimbic cortex was weak and disordered—very much like the brain activity seen in human depression. In particular, two types of brain activity, called theta and low-gamma oscillations, were not synchronized. To determine precisely what causes these abnormal oscillations, Sauer et al. took brain slices from depressed mice, and then stained them with dyes that showed the circuits in the prelimbic cortex more clearly. This revealed that depressed mice had developmental defects in a specific type of inhibitory neuron called fast-spiking interneurons—there were fewer of these cells, and the neurons that were there did not have the correct number of connections to other neurons. Further investigation showed that these neurons had difficulties receiving and releasing the chemical messengers that allow neurons to communicate, and Sauer et al. thought that this might cause the low-gamma oscillation problems. To confirm this theory, Sauer et al. created a computer model that simulated the defective interneurons. The simulations support the theory that the defects in the fast-spiking interneurons cause the abnormal low-gamma rhythms seen in depressed mice. In the future, a better understanding of the defects of inhibitory cells in DISC1 mutants and other mouse models of mental illness might open up new avenues for targeted drug design. As the prelimbic cortex combines inputs from various other brain areas, a further challenge will be to examine whether these inputs influence the activity of the prelimbic cortex and thus contribute to depression-related behavior. DOI: http://dx.doi.org/10.7554/eLife.04979.002