Abstract
AbstractCognitive decline during aging is correlated with a continuous loss of cells within the brain and especially within the hippocampus, which could be regenerated by adult neurogenesis. Here we show that genetic ablation of NF-κB resulted in severe defects in the neurogenic region (dentate gyrus) of the hippocampus. Despite increased stem cell proliferation, axogenesis, synaptogenesis and neuroprotection were hampered, leading to disruption of the mossy fiber pathway and to atrophy of the dentate gyrus during aging. Here, NF-κB controls the transcription of FOXO1 and PKA, regulating axogenesis. Structural defects culminated in behavioral impairments in pattern separation. Re-activation of NF-κB resulted in integration of newborn neurons, finally to regeneration of the dentate gyrus, accompanied by a complete recovery of structural and behavioral defects. These data identify NF-κB as a crucial regulator of dentate gyrus tissue homeostasis suggesting NF-κB to be a therapeutic target for treating cognitive and mood disorders.
Highlights
The hippocampus is crucial for the formation of spatial or episodic memory (Squire et al, 2004)
Cognitive decline during aging is correlated with a continuous loss of cells within the brain and especially within the hippocampus, which could be regenerated by adult neurogenesis
NF-κB controls the transcription of FOXO1 and Protein kinase A (PKA), regulating axogenesis
Summary
The hippocampus is crucial for the formation of spatial or episodic memory (Squire et al, 2004). Neurogenesis is a key-feature of the adult dentate gyrus, but the function of newborn neurons remains unclear (Deng et al, 2010). Whereas a lot of information on the role of NF- κB in neuronal process growth is already available, one of the main questions that remained to be answered is: what is the physiological importance of the regulation of axonal growth by NF-κB signaling for neuronal development in vivo (Gutierrez and Davies, 2011) This question will be addressed here in a special brain region, the dentate gyrus. Inhibition of NF-κB in both developmental stages leads to severe atrophy of the dentate gyrus in aging animals These data might explain why the neuronal circuit is damaged upon inactivation of NF-kB, because mossy fibers, the axons of granule cells, were degenerating and the dentate gyrus can not be regenerated by the addition of newborn neurons. Taken together our findings suggest that NF-κB might have therapeutic potential for reversing dentate gyrus dysfunction as observed in Alzheimers disease and mood disorders
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