Modulation of GABAA Receptor Signaling Increases Neurogenesis and Suppresses Anxiety through NFATc4
| Autor: | Kirsi Forsberg, Andrea Sabino, Mohamed Y. Elnaggar, Ceren Duman, Giorgia Quadrato, Simone Di Giovanni |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Mice Knockout Mice 129 Strain NFATC Transcription Factors GABAA receptor Neurogenesis General Neuroscience GABRA4 NFAT Articles Anxiety Hippocampal formation Biology Receptors GABA-A Hippocampus Mice Inbred C57BL Mice Transcriptional regulation biology.protein Animals GABAergic Transcription factor Neuroscience Signal Transduction |
| Zdroj: | Journal of Neuroscience. 34:8630-8645 |
| ISSN: | 1529-2401 0270-6474 |
| Popis: | 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 GABA(A) receptor (GABA(A)R) 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 GABA(A)R activity promotes hippocampal neurogenesis via the calcineurin/NFATc4 axis. Importantly, the NFATc4-dependent increase in hippocampal neurogenesis after GABA(A)R 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 GABA(A)R/NFATc4 axis is a druggable target for the therapy of emotional disorders. |
| Databáze: | OpenAIRE |
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