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The Journal of Neuroscience, September 24, 2008, 28(39):9870-9879; doi:10.1523/JNEUROSCI.2841-08.2008

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Development/Plasticity/Repair
Induction of Proneurotrophins and Activation of p75^NTR-Mediated Apoptosis via Neurotrophin Receptor-Interacting Factor in Hippocampal Neurons after Seizures

Marta Volosin,¹ Christy Trotter,¹ Andrea Cragnolini,¹ Rajappa S. Kenchappa,² Matthew Light,³ Barbara L. Hempstead,³ Bruce D. Carter,² and Wilma J. Friedman¹

¹Department of Biological Sciences, Rutgers University, Newark, New Jersey 07102, ²Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232, and ³Weill Medical College of Cornell University, New York, New York 10021

Correspondence should be addressed to Dr. Wilma J. Friedman, Department of Biological Sciences, Rutgers University, 225 University Avenue, Newark, NJ 07102. Email: wilmaf{at}andromeda.rutgers.edu

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.

Key words: neurotrophins; p75 neurotrophin receptor; apoptosis; signal transduction; NRIF; hippocampus

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Received June 20, 2008; revised Aug. 6, 2008; accepted Aug. 18, 2008.

Correspondence should be addressed to Dr. Wilma J. Friedman, Department of Biological Sciences, Rutgers University, 225 University Avenue, Newark, NJ 07102. Email: wilmaf{at}andromeda.rutgers.edu

This article has been cited by other articles:

				H. Yano, R. Torkin, L. A. Martin, M. V. Chao, and K. K. Teng Proneurotrophin-3 Is a Neuronal Apoptotic Ligand: Evidence for Retrograde-Directed Cell Killing J. Neurosci., November 25, 2009; 29(47): 14790 - 14802. [Abstract] [Full Text] [PDF]

				R. Masoudi, M. S. Ioannou, M. D. Coughlin, P. Pagadala, K. E. Neet, O. Clewes, S. J. Allen, D. Dawbarn, and M. Fahnestock Biological Activity of Nerve Growth Factor Precursor Is Dependent upon Relative Levels of Its Receptors J. Biol. Chem., July 3, 2009; 284(27): 18424 - 18433. [Abstract] [Full Text] [PDF]

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