A transcriptional constraint mechanism limits the homeostatic response to activity deprivation in mammalian neocortex.
A transcriptional constraint mechanism limits the homeostatic response to activity deprivation in mammalian neocortex.
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DOI：
10.7554/elife.74899
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发表时间：
2023-02-07
期刊：
影响因子：
7.7
通讯作者：
Nelson SB
中科院分区：
文献类型：
--
作者：
Valakh V;Wise D;Zhu XA;Sha M;Fok J;Van Hooser SD;Schectman R;Cepeda I;Kirk R;O'Toole SM;Nelson SB
健康的神经元网络依赖于稳态可塑性来维持稳定的放电率，尽管突触驱动发生了变化。然而，如果不适当或过度地激活这些机制，它们本身可能会破坏稳定。例如，长时间的活动剥夺可能导致反弹性多动和癫痫发作。虽然已经描述了许多形式的内稳态，但内稳态可塑性的大小是否以及如何受到限制仍然未知。在这里，我们揭示了负调节皮质网络稳态的PARbZIP家族的转录因子。在由缺乏所有这三个因素的基因敲除小鼠制成的皮质切片培养物中，用钙成像测量的对长时间活动撤回的网络反应要强得多，而基线活动没有变化。全细胞记录揭示了一个夸张的微型兴奋性突触电流的频率增加，反映了经常性兴奋性突触传递的上调增强。遗传分析表明，其中两个因素，Hlf和Tef，对于限制可塑性和防止危及生命的癫痫发作至关重要。这些数据表明，转录激活不仅需要许多形式的稳态可塑性，但也参与了抑制活动剥夺的反应。人类大脑由数十亿个神经细胞组成，这些神经细胞被称为神经元，它们相互接收和发送信号。为了避免受到过度刺激或刺激不足，神经元可以通过改变它们与其他神经细胞的连接方式来调整它们接收到的输入的强度。这个过程被称为稳态可塑性，被认为是正常大脑活动所必需的，因为它有助于保持神经元的传出信号相对恒定。然而，如果内稳态可塑性变得太强，过度补偿弱输入信号，则可能导致癫痫发作。因此，调节这一过程对大脑健康至关重要，但科学家们不知道它是否或如何被控制。为了解决这个问题，Valakh等人分析了缺乏传入信号的神经元中激活的基因，以找到调节稳态可塑性的蛋白质。这揭示了一类被称为转录因子（打开或关闭基因）的分子，它们限制了这一过程。在没有这些调节蛋白的小鼠的大脑样本中，神经元接受了两倍的输入，导致大脑活动增加，类似于癫痫发作期间观察到的情况。Valakh等人使用活小鼠证实了这一发现，这些小鼠在缺乏这些转录因子的情况下发生癫痫发作。这些发现表明，这种类型的调节，以保持稳态可塑性变得太强可能是重要的。随着大脑的发育，当神经元之间的连接强度迅速变化时，这一点尤其重要。转录因子的发现为激活或抑制稳态可塑性提供了潜在的靶点。这种控制可以帮助研究人员更好地了解这个过程是如何稳定大脑信号的。
Healthy neuronal networks rely on homeostatic plasticity to maintain stable firing rates despite changing synaptic drive. These mechanisms, however, can themselves be destabilizing if activated inappropriately or excessively. For example, prolonged activity deprivation can lead to rebound hyperactivity and seizures. While many forms of homeostasis have been described, whether and how the magnitude of homeostatic plasticity is constrained remains unknown. Here, we uncover negative regulation of cortical network homeostasis by the PARbZIP family of transcription factors. In cortical slice cultures made from knockout mice lacking all three of these factors, the network response to prolonged activity withdrawal measured with calcium imaging is much stronger, while baseline activity is unchanged. Whole-cell recordings reveal an exaggerated increase in the frequency of miniature excitatory synaptic currents reflecting enhanced upregulation of recurrent excitatory synaptic transmission. Genetic analyses reveal that two of the factors, Hlf and Tef, are critical for constraining plasticity and for preventing life-threatening seizures. These data indicate that transcriptional activation is not only required for many forms of homeostatic plasticity but is also involved in restraint of the response to activity deprivation. The human brain is made up of billions of nerve cells called neurons which receive and send signals to one another. To avoid being over- or under-stimulated, neurons can adjust the strength of the inputs they receive by altering how connected they are to other nerve cells. This process, known as homeostatic plasticity, is thought to be necessary for normal brain activity as it helps keep the outgoing signals of neurons relatively constant. However, homeostatic plasticity can lead to seizures if it becomes too strong and overcompensates for weak input signals. Regulating this process is therefore central to brain health, but scientists do not understand if or how it is controlled. To address this, Valakh et al. analyzed the genes activated in neurons lacking incoming signals to find proteins that regulate homeostatic plasticity. This revealed a class of molecules called transcription factors (which switch genes on or off) that constrain the process. In brain samples from mice without these regulatory proteins, neurons received twice as much input, leading to an increase in brain activity resembling that observed during seizures. Valakh et al. confirmed this finding using live mice, which developed seizures in the absence of these transcription factors. These findings suggest that this type of regulation to keep homeostatic plasticity from becoming too strong may be important. This could be especially vital as the brain develops, when the strength of connections between neurons changes rapidly. The discovery of the transcription factors involved provides a potential target for activating or restraining homeostatic plasticity. This control could help researchers better understand how the process stabilizes brain signaling.