Laboratory for NeuroRegeneration and Repair, Center for Neurology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72076 Tuebingen, Germany,
Laboratory for NeuroRegeneration and Repair, Center for Neurology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72076 Tuebingen, Germany, Graduate School for Cellular and Molecular Neuroscience, University of Tuebingen, 72074 Tuebingen, Germany, and.
J Neurosci. 2014 Jun 18;34(25):8630-45. doi: 10.1523/JNEUROSCI.0047-14.2014.
Correlative evidence suggests that GABAergic signaling plays an important role in the regulation of activity-dependent hippocampal neurogenesis and emotional behavior in adult mice. However, whether these are causally linked at the molecular level remains elusive. Nuclear factor of activated T cell (NFAT) proteins are activity-dependent transcription factors that respond to environmental stimuli in different cell types, including hippocampal newborn neurons. Here, we identify NFATc4 as a key activity-dependent transcriptional regulator of GABA signaling in hippocampal progenitor cells via an unbiased high-throughput genome-wide study. Next, we demonstrate that GABAA receptor (GABAAR) signaling modulates hippocampal neurogenesis through NFATc4 activity, which in turn regulates GABRA2 and GABRA4 subunit expression via binding to specific promoter responsive elements, as assessed by ChIP and luciferase assays. Furthermore, we show that selective pharmacological enhancement of GABAAR activity promotes hippocampal neurogenesis via the calcineurin/NFATc4 axis. Importantly, the NFATc4-dependent increase in hippocampal neurogenesis after GABAAR stimulation is required for the suppression of the anxiety response in mice. Together, these data provide a novel molecular insight into the regulation of the anxiety response in mice, suggesting that the GABAAR/NFATc4 axis is a druggable target for the therapy of emotional disorders.
相关证据表明，GABA 能信号在调节成年小鼠活性依赖的海马神经发生和情绪行为方面发挥着重要作用。然而，这些在分子水平上是否存在因果关系仍不清楚。活化 T 细胞核因子（NFAT）蛋白是一种活性依赖的转录因子，可对不同细胞类型（包括海马新生神经元）中的环境刺激作出反应。在这里，我们通过一项无偏的高通量全基因组研究，确定 NFATc4 是海马祖细胞中 GABA 信号的关键活性依赖转录调节剂。接下来，我们证明 GABAAR 信号通过 NFATc4 活性调节海马神经发生，进而通过结合特定的启动子反应元件调节 GABRA2 和 GABRA4 亚基的表达，如 ChIP 和荧光素酶测定所评估的那样。此外，我们表明选择性地增强 GABAAR 活性通过钙调神经磷酸酶/NFATc4 轴促进海马神经发生。重要的是，GABAAR 刺激后 NFATc4 依赖性海马神经发生的增加是抑制小鼠焦虑反应所必需的。总之，这些数据为调节小鼠焦虑反应提供了新的分子见解，表明 GABAAR/NFATc4 轴是治疗情绪障碍的药物靶点。
