Nuclear factor of activated T cells (NFATc4) is required for BDNF-dependent survival of adult-born neurons and spatial memory formation in the hippocampus

Abstract

New neurons generated in the adult dentate gyrus are constantly integrated into the hippocampal circuitry and activated during encoding and recall of new memories. Despite identification of extracellular signals that regulate survival and integration of adult-born neurons such as neurotrophins and neurotransmitters, the nature of the intracellular modulators required to transduce those signals remains elusive. Here, we provide evidence of the expression and transcriptional activity of nuclear factor of activated T cell c4 (NFATc4) in hippocampal progenitor cells. We show that NFATc4 calcineurin-dependent activity is required selectively for survival of adult-born neurons in response to BDNF signaling. Indeed, cyclosporin A injection and stereotaxic delivery of the BDNF scavenger TrkB-Fc in the mouse dentate gyrus reduce the survival of hippocampal adult-born neurons in wild-type but not in NFATc4 −/− mice and do not affect the net rate of neural precursor proliferation and their fate commitment. Furthermore, associated with the reduced survival of adult-born neurons, the absence of NFATc4 leads to selective defects in LTP and in the encoding of hippocampal-dependent spatial memories. Thus, our data demonstrate that NFATc4 is essential in the regulation of adult hippocampal neurogenesis and identify NFATc4 as a central player of BDNFdriven prosurvival signaling in hippocampal adult-born neurons.adult neurogenesis | long-term potentiation | transcription | neural stem cells N ew adult hippocampal neurons are generated continuously as a result of a finely tuned and dynamic balance among neural stem cell proliferation, survival, differentiation, and migration. Once integrated into the dentate gyrus (DG) and hippocampal circuitry, adult-born neurons are likely selected for encoding new information that contributes to learning and memory (1-4). Several extrinsic regulators such as neurotrophins and neurotransmitters have been identified as pivotal in the regulation of survival and synaptic integration of new neurons in the adult hippocampus (5-10). However, much less is known about transcription factors and intracellular signaling required to integrate and transduce those signals. Among a number of potential intracellular mechanisms, Ca 2+ mobilization plays a pivotal role during neuronal survival, maturation, and synapse formation.A wide range of stimuli can increase the release of stored intracellular calcium including the binding of growth factors to their receptors and activation of voltage-dependent ion channels (11). A rise in intracellular calcium turns on the phosphatase calcineurin, which rapidly dephosphorylates the four members of the cytoplasmic nuclear factor of activated T cell (NFAT) family (NFATc1-4), promoting their nuclear translocation and transcriptional activation (12)(13)(14). NFAT family members were described first as essential components of T-cells activation and later as important regulators for the initiation and coordination of the immune response, including B cells and natural killer cells...

Nerve Growth Factor (NGF) Regulates Activity of Nuclear Factor of Activated T-cells (NFAT) in Neurons via the Phosphatidylinositol 3-Kinase (PI3K)-Akt-Glycogen Synthase Kinase 3β (GSK3β) Pathway

“…These findings are in good agreement with our previous molecular and functional data indicating that NFATc3 is the predominant NFAT isoform in DRG neurons (7,33). However, given that the expression and roles of specific NFAT isoforms vary among different types of neurons (4,8,12,13,28), it is likely that other NFAT isoforms are also regulated by neurotrophins. For example, NFATc4 is targeted by BDNF in hippocampal neurons (12,13,28).…”

“…However, given that the expression and roles of specific NFAT isoforms vary among different types of neurons (4,8,12,13,28), it is likely that other NFAT isoforms are also regulated by neurotrophins. For example, NFATc4 is targeted by BDNF in hippocampal neurons (12,13,28). By monitoring the nuclear translocation of EGFP-NFATc3 in DRG neurons in real time, we found that NGF and GSK3␤ inhibited nuclear export of NFATc3 but had no detectable effect on the rate of nuclear import of NFATc3 (Figs.…”

“…For example, NGF and brainderived neurotrophic factor (BDNF) stimulate NFAT-dependent expression of inositol 1,4,5-trisphosphate receptor 1, BDNF, cyclooxygenase-2, and plasminogen activation inhibitor-1 in peripheral and central neurons (15,28,29). BDNF-dependent survival of adult hippocampal neurons and the formation of spatial memory have also been reported to require NFAT activation (13). Furthermore, NFAT is essential for NGF-dependent axonal growth, and deletion of NFAT isoforms NFATc2, NFATc3, and NFATc4 disrupts neurite outgrowth (4).…”

Control of neuronal apoptosis by reciprocal regulation of NFATc3 and Trim17

“…Notably, the nuclear factor of activated T cell (NFAT) transcription factors have an important role in the development of the nervous system 7,8 and in the control of the survival/death fate of neurons. [9][10][11][12][13][14] The NFAT family comprises four calcium/calcineurindependent transcription factors that are encoded by four closely related genes. [15][16][17] NFAT proteins are expressed in most mammalian tissues, with the different members of the family being present in distinct but overlapping sets of cell types.…”

“…Both NFATc3 and NFATc4 have been shown to have either proapoptotic or antiapoptotic effects, depending on the physiologic and cellular context. [9][10][11][12][13][14][20][21][22] However, the mechanisms that regulate their activity in response to apoptotic stimuli and the target genes that mediate their differential effects on neuronal apoptosis are mostly unknown.…”