Induction of Proneurotrophins and Activation of p75NTR-Mediated Apoptosis via Neurotrophin Receptor-Interacting Factor in Hippocampal Neurons after Seizures
Open accessAbstract
Seizure-induced damage elicits a loss of hippocampal neurons mediated to a great extent by the p75 neurotrophin receptor (NTR). Proneurotrophins, which are potent apoptosis-inducing ligands for p75 NTR, were increased in the hippocampus, particularly in astrocytes, by pilocarpine-induced seizures; and infusion of anti-pro-NGF dramatically attenuated neuronal loss after seizures. The p75 NTR is expressed in many different cell types in the nervous system, and can mediate a variety of different cellular functions by recruiting specific intracellular binding proteins to activate distinct signaling pathways. In this study, we demonstrate that neurotrophin receptor-interacting factor (NRIF) mediates apoptotic signaling via p75 NTR in hippocampal neurons in vitro and in vivo. After seizure-induced injury,NRIF−/−mice showed an increase in p75 NTR expression in the hippocampus; however, these neurons failed to undergo apoptosis in contrast to wild-type mice. Treatment of cultured hippocampal neurons with proneurotrophins induced association of NRIF with p75 NTR and subsequent translocation of NRIF to the nucleus, which was dependent on cleavage of the receptor. Neurons lacking NRIF were resistant to p75 NTR-mediated apoptosis in vitro and in vivo. In addition, we demonstrate some mechanistic differences in p75 NTR signaling in hippocampal neurons compared with other cell types. Overall, these studies demonstrate the requirement for NRIF to signal p75 NTR-mediated apoptosis of hippocampal neurons and that blocking pro-NGF can inhibit neuronal loss after seizures.
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Pro-neurotrophins induce apoptosis when Trk receptors are absent via interaction between sortilin and p75NTR.
“Pro-neurotrophins induce apoptosis in the absence of Trk receptors via interaction between sortilin and p75NTR33,82,86,87.”
From Neuronal plasticity and neurotrophic factors in drug responses (2017) · cites this paper as [86]
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- Authors
- Volosin, M., Trotter, C., Cragnolini, A., Kenchappa, R. S., Light, M., Hempstead, B. L., Carter, B. D., & Friedman, W. J.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- Vanderbilt University (US)
- Cornell University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-09-24
- Volume
- 28
- Issue
- 39
- Pages
- 9870-9879
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2578816
- OpenAlex
- W1979962409
- Cited by
- 149
- References
- 54
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 7 · 2023: 3 · 2022: 5 · 2021: 10 · 2020: 4 · 2019: 11 · 2018: 6 · 2017: 14 · 2016: 15 · 2015: 8 · 2014: 12 · 2013: 9 · 2012: 7
- FWCI
- 4.18
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS038220, NS03880, NS045556, R01NS045556)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- p75 neurotrophin receptor, apoptosis, hippocampal neurons, pilocarpine-induced seizures, neuronal loss, astrocytes, receptor cleavage
- MeSH terms
- Animals, Cell Survival, Cells, Cultured, Disease Models, Animal, DNA-Binding Proteins, Embryo, Mammalian, Female, Fluoresceins, Hippocampus, Male, Nerve Growth Factors, Neurons, Organic Chemicals, Pilocarpine, Pregnancy, Protein Precursors, Seizures, Time Factors, Apoptosis, Mice, Knockout, Receptor, Nerve Growth Factor, Nerve Growth Factor, Electrophoretic Mobility Shift Assay, Intracellular Signaling Peptides and Proteins, Mice, Rats
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