title: Caffeine-mediated BDNF release regulates long-term synaptic plasticity through activation of IRS2 signaling.
abstract: Caffeine has cognitive-enhancing properties with effects on learning and memory, concentration, arousal and mood. These effects imply changes at circuital and synaptic level, but the mechanism by which caffeine modifies synaptic plasticity remains elusive. Here we report that caffeine, at concentrations representing moderate to high levels of consumption in humans, induces an NMDA receptor-independent form of LTP (CAFLTP) in the CA1 region of the hippocampus by promoting calcium-dependent secretion of BDNF, which subsequently activates TrkB-mediated signaling required for the expression ofCAFLTP. Our data include the novel observation that insulin receptor substrate 2 (IRS2) is phosphorylated during induction ofCAFLTP, a process that requires cytosolic free Ca2+. Consistent with the involvement of IRS2 signals in caffeine-mediated synaptic plasticity, phosphorylation of Akt (Ser473) in response to LTP induction is defective in Irs2-/-mice, demonstrating that these plasticity changes are associated with downstream targets of the phosphoinositide 3-kinase (PI3K) pathway. These findings indicate that TrkB-IRS2 signals are essential for activation of PI3K during the induction of LTP by caffeine.
authors.affiliation: Laboratory of Neurophysiology and Synaptic Plasticity, Castilla-La Mancha Science and Technology Park (PCYTCLM), Institute for Research in Neurological Disabilities (IDINE), University of Castilla-La Mancha, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Lao-Peregrín
authors.affiliation: Laboratory of Neurophysiology and Synaptic Plasticity, Castilla-La Mancha Science and Technology Park (PCYTCLM), Institute for Research in Neurological Disabilities (IDINE), University of Castilla-La Mancha, Spain.
authors.forename: Jesús Javier
authors.initials: JJ
authors.lastname: Ballesteros
authors.affiliation: Laboratory of Neurophysiology and Synaptic Plasticity, Castilla-La Mancha Science and Technology Park (PCYTCLM), Institute for Research in Neurological Disabilities (IDINE), University of Castilla-La Mancha, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Fernández
authors.affiliation: Laboratory of Neurophysiology and Synaptic Plasticity, Castilla-La Mancha Science and Technology Park (PCYTCLM), Institute for Research in Neurological Disabilities (IDINE), University of Castilla-La Mancha, Spain.
authors.forename: Alfonsa
authors.initials: A
authors.lastname: Zamora-Moratalla
authors.affiliation: Departament de Biomedicina, Facultat de Medicina, Universitat de Barcelona, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain.|Centro de Investigación Biomédica en Red (CIBER) sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.|Institut de Neurociències, Universitat de Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Saavedra
authors.affiliation: Laboratory of Neurophysiology and Synaptic Plasticity, Castilla-La Mancha Science and Technology Park (PCYTCLM), Institute for Research in Neurological Disabilities (IDINE), University of Castilla-La Mancha, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Gómez Lázaro
authors.affiliation: Departament de Biomedicina, Facultat de Medicina, Universitat de Barcelona, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain.|Centro de Investigación Biomédica en Red (CIBER) sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.|Institut de Neurociències, Universitat de Barcelona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Pérez-Navarro
authors.affiliation: Centro de Investigación Príncipe Felipe, CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain.
authors.forename: Deborah
authors.initials: D
authors.lastname: Burks
authors.affiliation: Laboratory of Neurophysiology and Synaptic Plasticity, Castilla-La Mancha Science and Technology Park (PCYTCLM), Institute for Research in Neurological Disabilities (IDINE), University of Castilla-La Mancha, Spain.
authors.forename: Eduardo D
authors.initials: ED
authors.lastname: Martín
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000187:drug effects / Q000378:metabolism*; D002110:Caffeine / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D005260:Female; D055504:Insulin Receptor Substrate Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D023421:Models, Animal; D009473:Neuronal Plasticity / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D000697:Central Nervous System Stimulants; D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D002110:Caffeine
keywords: NMDA-independent synaptic plasticity; PI3K-AKT pathway; TrkB receptor; hippocampus; insulin receptors