title: proBDNF and p75NTR Control Excitability and Persistent Firing of Cortical Pyramidal Neurons.
abstract: Persistent firing of entorhinal cortex (EC) pyramidal neurons is a key component of working and spatial memory. We report here that a pro-brain-derived neurotrophic factor (proBDNF)-dependent p75NTR signaling pathway plays a major role in excitability and persistent activity of pyramidal neurons in layer V of the EC. Using electrophysiological recordings, we show that proBDNF suppresses persistent firing in entorhinal slices from wild-type mice but not from p75NTR-null mice. Conversely, function-blocking proBDNF antibodies enhance excitability of pyramidal neurons and facilitate their persistent firing, and acute exposure to function-blocking p75NTR antibodies results in enhanced firing activity of pyramidal neurons. Genetic deletion of p75NTR specifically in neurons or during adulthood also induces enhanced excitability and persistent activity, indicating that the proBDNF-p75NTR signaling cascade functions within adult neurons to inhibit pyramidal activity. Phosphatidylinositol 4,5-bisphosphate (PIP2)-sensitive transient receptor potential canonical channels play a critical role in mediating persistent firing in the EC and we hypothesized that proBDNF-dependent p75NTR activation regulates PIP2 levels. Accordingly, proBDNF decreases cholinergic calcium responses in cortical neurons and affects carbachol-induced depletion of PIP2. Further, we show that the modulation of persistent firing by proBDNF relies on a p75NTR-Rac1-PI4K pathway. The hypothesis that proBDNF and p75NTR maintain network homeostasis in the adult CNS was tested in vivo and we report that p75NTR-null mice show improvements in working memory but also display an increased propensity for severe seizures. We propose that the proBDNF-p75NTR axis controls pyramidal neuron excitability and persistent activity to balance EC performance with the risk of runaway activity.
  
  
  CONCLUSIONS
  Persistent firing of entorhinal cortex (EC) pyramidal neurons is required for working memory. We report here that pro-brain-derived neurotrophic factor (proBDNF) activates p75NTR to induce a Rac1-dependent and phosphatidylinositol 4,5-bisphosphate-dependent signaling cascade that suppresses persistent activity. Conversely, using loss-of-function approaches, we find that endogenous proBDNF or p75NTR activation strongly decreases pyramidal neuron excitability and persistent firing, suggesting that a physiological role of this proBDNF-p75NTR cascade may be to regulate working memory in vivo. Consistent with this, mice rendered null for p75NTR during adulthood show improvements in working memory but also display an increased propensity for severe seizures. We propose that by attenuating EC network performance, the proBDNF-p75NTR signaling cascade reduces the probability of epileptogenesis.
authors.affiliation: Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada H3A2B4, and.
authors.forename: Julien
authors.initials: J
authors.lastname: Gibon
authors.affiliation: Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada H3A2B4, and.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Buckley
authors.affiliation: Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada H3A2B4, and.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Unsain
authors.affiliation: Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Vesa
authors.initials: V
authors.lastname: Kaartinen
authors.affiliation: Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada H3A2B4, and philippe.seguela@mcgill.ca phil.barker@mcgill.ca.
authors.forename: Philippe
authors.initials: P
authors.lastname: Séguéla
authors.affiliation: Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada H3A2B4, and philippe.seguela@mcgill.ca phil.barker@mcgill.ca.
authors.forename: Philip A
authors.identifier: http://orcid.org/0000-0002-3444-7551
authors.initials: PA
authors.lastname: Barker
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D018679:Cholinergic Agonists / Q000494:pharmacology; D003292:Convulsants / Q000633:toxicity; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology*; D010433:Pentylenetetrazole / Q000633:toxicity; D054803:Phospholipase C delta / Q000235:genetics / Q000378:metabolism; D010862:Pilocarpine / Q000633:toxicity; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology
chemical_list: D000634:Aminoquinolines; D019208:Brain-Derived Neurotrophic Factor; D018679:Cholinergic Agonists; D003292:Convulsants; C487513:NSC 23766; D011498:Protein Precursors; D011743:Pyrimidines; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; C426674:brain-derived neurotrophic factor precursor; D010862:Pilocarpine; D002217:Carbachol; D054803:Phospholipase C delta; C518025:Plcd1 protein, mouse; D010433:Pentylenetetrazole
keywords: entorhinal cortex; epilepsy; p75NTR; persistent firing; proBDNF; working memory