Abstract
Stress leads to brain pathology including hippocampal degeneration, cognitive dysfunction, and potential mood disorders. Hippocampal CA3, a most stress-vulnerable region, consists of pyramidal neurons that regulate cognitive functions e.g. learning and memory. These CA3 neurons express high levels of the neuroprotective protein, neurotrophic factor-α1 (NF-α1), also known as carboxypeptidase E (CPE), and receive contacts from granule cell projections that release BDNF which has neuroprotective activity. Whether NF-α1-CPE and/or BDNF are critical in protecting these CA3 neurons against severe stress-induced cell death is unknown. Here we show that social combined with the physical stress of maternal separation, ear tagging, and tail snipping at weaning in 3-week-old mice lacking NF-α1-CPE, led to complete hippocampal CA3 degeneration, despite having BDNF and active phosphorylated TrkB receptor levels similar to WT animals. Mice administered TrkB inhibitor, ANA12 which blocked TrkB phosphorylation showed no degeneration of the CA3 neurons after the weaning stress paradigm. Furthermore, transgenic knock-in mice expressing CPE-E342Q, an enzymatically inactive form, replacing NF-α1-CPE, showed no CA3 degeneration and exhibited normal learning and memory after the weaning stress, unlike NF-α1-CPE-KO mice. Mechanistically, we showed that radio-labeled NF-α1-CPE bound HT22 hippocampal cells in a saturable manner and with high affinity (Kd = 4.37 nM). Subsequently, treatment of the HT22cpe−/− cells with NF-α1-CPE or CPE-E342Q equivalently activated ERK signaling and increased BCL2 expression to protect these neurons against H2O2-or glutamate-induced cytotoxicity. Our findings show that NF-α1-CPE is more critical compared to BDNF in protecting CA3 pyramidal neurons against stress-induced cell death and cognitive dysfunction, independent of its enzymatic activity.
Highlights
Hippocampal degeneration, impaired neuronal network, reduced neurogenesis, and cognitive dysfunction are pathological changes that occur after stress[1,2] and in neurodegenerative disorders such as Alzheimer’s disease (AD)[2,3]
Our findings show that neurotrophic factor-α1 (NF-α1)-carboxypeptidase E (CPE) is more critical compared to BDNF in protecting CA3 pyramidal neurons against stress-induced cell death and cognitive dysfunction, independent of its enzymatic activity
Based on the studies of McEwen’s group[1], we propose that emotional and physical stress incurred during the weaning paradigm, or restraint stress, which causes a huge increase in glucocorticoid release (Supplementary Fig. S1), would stimulate the granule cells in the dentate gyrus to release glutamate via the mossy fibers that contact the pyramidal neurons in the CA3 region
Summary
Hippocampal degeneration, impaired neuronal network, reduced neurogenesis, and cognitive dysfunction are pathological changes that occur after stress[1,2] and in neurodegenerative disorders such as Alzheimer’s disease (AD)[2,3]. Each neurotrophic factor is highly expressed and involved. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
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