TY - JOUR
T1 - Induction of proneurotrophins and activation of p75NTR-mediated apoptosis via neurotrophin receptor-interacting factor in hippocampal neurons after seizures
AU - Volosin, Marta
AU - Trotter, Christy
AU - Cragnolini, Andrea
AU - Kenchappa, Rajappa S.
AU - Light, Matthew
AU - Hempstead, Barbara L.
AU - Carter, Bruce D.
AU - Friedman, Wilma J.
PY - 2008/9/24
Y1 - 2008/9/24
N2 - 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 p75NTR, 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 p75NTR is expressed inmanydifferent 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 p75NTR in hippocampal neurons in vitro and in vivo. After seizure-induced injury, NRIF-/- mice showed an increase in p75NTR 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 p75NTR and subsequent translocation of NRIF to the nucleus, which was dependent on cleavage of the receptor. Neurons lacking NRIF were resistant to p75NTR-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.
AB - 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 p75NTR, 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 p75NTR is expressed inmanydifferent 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 p75NTR in hippocampal neurons in vitro and in vivo. After seizure-induced injury, NRIF-/- mice showed an increase in p75NTR 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 p75NTR and subsequent translocation of NRIF to the nucleus, which was dependent on cleavage of the receptor. Neurons lacking NRIF were resistant to p75NTR-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.
KW - Apoptosis
KW - Hippocampus
KW - NRIF
KW - Neurotrophins
KW - Signal transduction
KW - p75 neurotrophin receptor
UR - http://www.scopus.com/inward/record.url?scp=55749104402&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=55749104402&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.2841-08.2008
DO - 10.1523/JNEUROSCI.2841-08.2008
M3 - Article
C2 - 18815271
AN - SCOPUS:55749104402
SN - 0270-6474
VL - 28
SP - 9870
EP - 9879
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 39
ER -