In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 23 ( 2012-06-05)
Abstract:
Our experiments define crucial molecular events involved in BDNF-promoted survival signaling in hippocampal neural stem cells. Moreover, they raise the possibility that BDNF, calcineurin, and NFATc4 offer promising targets for developing strategies aimed at reversing memory-formation dysfunctions, such those experienced during normal aging or resulting from neurological disorders, by enhancing the survival of endogenous precursor cells and thus promoting the recovery of memory formation. Here we show that NFATc4 is expressed and acts as a transcription factor in hippocampal progenitor cells and that its activity depends on calcineurin. We show that NFATc4 calcineurin-dependent activity is required selectively for survival of adult-born neurons in response to BDNF signaling ( Fig. P1 ). Cyclosporin A, a calcineurin inhibitor, and inhibition of BDNF in the mouse dentate gyrus reduced the survival of hippocampal adult-born neurons in the presence but not in the absence of NFATc4. Interestingly, the absence of NFATc4 did not affect other steps of neural progenitor cell development such as proliferation and fate commitment. Importantly, we found that, the absence of NFATc4, associated with the reduced survival of adult-born neurons in the adult dentate gyrus, also leads to selective defects in the encoding of hippocampal-dependent spatial memories ( Fig. P1 ). Among different intracellular mechanisms, Ca 2+ mobilization is known to be required for neuronal survival, maturation, and synapse formation. When elevated, intracellular Ca 2+ activates the protein phosphatase calcineurin, which removes phosphate groups from the four cytoplasmic NFAT family members (NFATc1-4), causing them to relocate from the cytoplasm to the nucleus where they activate gene expression. As activity-dependent transcription factors, NFAT proteins are important for the ability of new tissues to modify their phenotypes in response to environmental changes ( 2 ). Thus, they also appear ideally suited to transduce the extracellular signals present in neurogenic niches that support the maintenance and differentiation processes undergone by hippocampal progenitor cells. Further, NFATc4 is expressed in the dentate gyrus ( 3 ) and is activated by BDNF and NMDA to mediate neural survival and synaptic plasticity ( 4 , 5 ). Therefore, we reasoned that BDNF, calcineurin, and NFATc4 might play a pivotal role in the regulation of adult hippocampal neurogenesis and hippocampal-dependent memory formation and learning. In the adult mammalian brain, neurogenesis creates new neurons (adult-born neurons) as a result of a finely tuned and dynamic balance among neural stem cells proliferation, survival, and differentiation. The remarkable plasticity of this process allows the brain to adjust to environmental stimuli. The subgranular zone of the dentate gyrus is the area where new neurons are integrated constantly into the hippocampal circuitry, which is crucial for forming spatial memory. These neurons are activated when new memories are encoded and then recalled ( 1 ). Several extracellular cues modulating survival and integration of adult-born hippocampal neurons, such as neurotrophins and neurotransmitters, have been identified. However, the players within the intracellular signaling pathways that integrate and transduce those signals have been characterized only partially. To develop therapies for preventing and correcting pathological cognitive processes, we aimed to define the molecules involved. Here, we show that the neurotrophin BDNF, which promotes the survival, growth, and differentiation of new neurons, exerts its prosurvival effects by signaling to the transcription factor, nuclear factor of activated T cells (NFATc4).
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1202068109
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2012
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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