title: Modulation of GABAA receptor signaling increases neurogenesis and suppresses anxiety through NFATc4.
abstract: 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.
authors.affiliation: Laboratory for NeuroRegeneration and Repair, Center for Neurology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72076 Tuebingen, Germany, giorgia.quadrato@uni-tuebingen.de s.di-giovanni@imperial.ac.uk.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Quadrato
authors.affiliation: 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.
authors.forename: Mohamed Y
authors.initials: MY
authors.lastname: Elnaggar
authors.affiliation: 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.
authors.forename: Ceren
authors.initials: C
authors.lastname: Duman
authors.affiliation: Laboratory for NeuroRegeneration and Repair, Center for Neurology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72076 Tuebingen, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sabino
authors.affiliation: Laboratory for NeuroRegeneration and Repair, Center for Neurology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72076 Tuebingen, Germany.
authors.forename: Kirsi
authors.initials: K
authors.lastname: Forsberg
authors.affiliation: Laboratory for NeuroRegeneration and Repair, Center for Neurology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72076 Tuebingen, Germany, Molecular Neuroregeneration, Division of Brain Sciences, Department of Medicine, Imperial College London, London W12 ONN, United Kingdom giorgia.quadrato@uni-tuebingen.de s.di-giovanni@imperial.ac.uk.
authors.forename: Simone
authors.initials: S
authors.lastname: Di Giovanni
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology*; D011963:Receptors, GABA-A / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C493920:Gabra2 protein, mouse; C546261:Gabra4 protein, mouse; D050778:NFATC Transcription Factors; C467907:Nfatc4 protein, mouse; D011963:Receptors, GABA-A
keywords: GABAergic signaling; NFATc4; adult hippocampal neurogenesis; anxiety