Brain-Derived Neurotrophic Factor Activation of NFAT (Nuclear Factor of Activated T-Cells)-Dependent Transcription: A Role for the Transcription Factor NFATc4 in Neurotrophin-Mediated Gene Expression

Abstract

A member of the neurotrophin family, brain-derived neurotrophic factor (BDNF) regulates neuronal survival and differentiation during development. Within the adult brain, BDNF is also important in neuronal adaptive processes, such as the activity-dependent plasticity that underlies learning and memory. These long-term changes in synaptic strength are mediated through alterations in gene expression. However, many of the mechanisms by which BDNF is linked to transcriptional and translational regulation remain unknown. Recently, the transcription factor NFATc4 (nuclear factor of activated T-cells isoform 4) was discovered in neurons, where it is believed to play an important role in long-term changes in neuronal function. Interestingly, NFATc4 is particularly sensitive to the second messenger systems activated by BDNF. Thus, we hypothesized that NFAT-dependent transcription may be an important mediator of BDNF-induced plasticity. In cultured rat CA3-CA1 hippocampal neurons, BDNF activated NFAT-dependent transcription via TrkB receptors. Inhibition of calcineurin blocked BDNF-induced nuclear translocation of NFATc4, thus preventing transcription. Further, phospholipase C was a critical signaling intermediate between BDNF activation of TrkB and the initiation of NFAT-dependent transcription. Both inositol 1,4,5-triphosphate (IP3)-mediated release of calcium from intracellular stores and activation of protein kinase C were required for BDNF-induced NFAT-dependent transcription. Finally, increased expression of IP3 receptor 1 and BDNF after neuronal exposure to BDNF was linked to NFAT-dependent transcription. These results suggest that NFATc4 plays a crucial role in neurotrophin-mediated synaptic plasticity.

Distinct Activation Properties of the Nuclear Factor of Activated T-cells (NFAT) Isoforms NFATc3 and NFATc4 in Neurons

“…Stimulation of cortical neurons with NMDA induced NFATc3 and NFATc4 nuclear translocation, although the time course of translocation was not examined (21). Treatment of hippocampal neurons with brain-derived neurotrophic factor also induced NFATc4 nuclear translocation that was independent of VGCC activity (47). Importantly, the rate and amplitude of NFATc4 nuclear translocation were not compared with that of other NFAT isoforms in these studies.…”

“…Here, we describe the differential regulation of the two most commonly studied NFAT isoforms in neurons, NFATc3 and NFATc4 (5,6,20,21,23,(45)(46)(47)(48)(49)(50)(51). We find that although NFATc3 is rapidly dephosphorylated and translocates to the nucleus upon depolarization, NFATc4 remains phosphorylated and localized to the cytosol.…”

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

“…The finding that NGF potentiates NFAT activation by attenuating NFAT kinase activity is novel, with previous studies having focused on the importance of a neurotrophin-induced increase in [Ca 2ϩ ] i for NFAT activation (15,28). Indeed, Groth et al (15,28) showed that another major neurotrophin, BDNF, activates NFAT-mediated transcription in hippocampal and spinal cord neurons and that these effects can be abolished by inhibiting either PLC or the endoplasmic reticulum Ca 2ϩ -ATPase.…”

“…Recent studies have demonstrated that not only electrical activity and intracellular Ca 2ϩ , but also neurotrophins, in particular nerve growth factor (NGF), potently regulate NFAT function in neurons (4,15,28). 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).…”

“…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).…”