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 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.

NFAT transcription factors regulate survival, proliferation, migration, and differentiation of neural precursor cells

“…Thus, heart valve development, angiogenesis, immune system maturation and bone formation are processes regulated by NFAT signaling (Graef et al, ). In addition, previous evidence implicates NFAT in neuronal differentiation, as the suppression of the anxiety response by GABA involves stimulation of neurogenesis by NFATc4 activation (Quadrato et al, ). Also in agreement with our results, electroporation of a dominant‐negative NFAT protein in chick eggs reduces the number of TUJ‐1‐positive cells in the embryonic neural tube.…”

“…Moreover, in the immune system NFAT proteins are key factors for thymocyte development (Graef et al, ; Macian, ). Regarding the brain, the stimulation of axonal outgrowth by netrins and neurotrophins fails in mice lacking NFATc2, c3, and c4 (Graef et al, ), and there is evidence of the essential role played by the calcineurin/NFATc4 pathway in the induction of neurogenesis by GABA signaling in the hippocampus (Quadrato et al, ). Thus, accumulated data indicate that NFAT signaling favors proliferation or differentiation of precursor cells depending on the developmental stage and cell type analyzed.…”

Correcting miR92a-vGAT-Mediated GABAergic Dysfunctions Rescues Human Tau-Induced Anxiety in Mice

“…In the synaptosome fraction, a correlated reduction of vGAT with GABA was also detected, whereas the level of PSD95 (a postsynaptic marker) was not changed ( Figure 3B). As GABAA receptors also play important roles in anxiety, 39,40 we analyzed the protein levels of GABAA subunits (GABAARa1 and GABAARb1) in the membrane fraction, but no significant change was found ( Figure 3B). These data suggest that vGAT deficit may underlie the htau-induced GABA reduction.…”

Xiao Yao San Improves the Anxiety-Like Behaviors of Rats Induced by Chronic Immobilization Stress: The Involvement of the JNK Signaling Pathway in the Hippocampus

“…19) In a rat experiment, the ventral hippocampal-medial prefrontal pathway, the GABAA receptor, and Galanin receptor 2 played a key role in anxiety. [20][21][22][23] The MAPK signaling pathway is involved in many pathological processes. JNK is part of this pathway and plays important roles in cell apoptosis and neurosystemic diseases.…”