RT Journal Article
SR Electronic
T1 Modulation of GABAA Receptor Signaling Increases Neurogenesis and Suppresses Anxiety through NFATc4
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 8630
OP 8645
DO 10.1523/JNEUROSCI.0047-14.2014
VO 34
IS 25
A1 Giorgia Quadrato
A1 Mohamed Y. Elnaggar
A1 Ceren Duman
A1 Andrea Sabino
A1 Kirsi Forsberg
A1 Simone Di Giovanni
YR 2014
UL http://www.jneurosci.org/content/34/25/8630.abstract
AB 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.