title: Early Alterations of Hippocampal Neuronal Firing Induced by Abeta42.
abstract: We studied the effect of Amyloid β 1-42 oligomers (Abeta42) on Ca2+ dependent excitability profile of hippocampal neurons. Abeta42 is one of the Amyloid beta peptides produced by the proteolytic processing of the amyloid precursor protein and participates in the initiating event triggering the progressive dismantling of synapses and neuronal circuits. Our experiments on cultured hippocampal network reveal that Abeta42 increases intracellular Ca2+ concentration by 46% and inhibits firing discharge by 19%. More precisely, Abeta42 differently regulates ryanodine (RyRs), NMDA receptors (NMDARs), and voltage gated calcium channels (VGCCs) by increasing Ca2+ release through RyRs and inhibiting Ca2+ influx through NMDARs and VGCCs. The overall increased intracellular Ca2+ concentration causes stimulation of K+ current carried by big conductance Ca2+ activated potassium (BK) channels and hippocampal network firing inhibition. We conclude that Abeta42 alters neuronal function by means of at least 4 main targets: RyRs, NMDARs, VGCCs, and BK channels. The development of selective modulators of these channels may in turn be useful for developing effective therapies that could enhance the quality of life of AD patients during the early onset of the pathology.
authors.affiliation: Department of Drug Science and Technology, Torino University, Corso Raffaello 30, 10125 Torino, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Gavello
authors.affiliation: Department of Drug Science and Technology, Torino University, Corso Raffaello 30, 10125 Torino, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Calorio
authors.affiliation: Department of Drug Science and Technology, Torino University, Corso Raffaello 30, 10125 Torino, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Franchino
authors.affiliation: Department of Chemistry Via Pietro Giuria 7, Torino University, 10125 Torino, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Cesano
authors.affiliation: Department of Drug Science and Technology, Torino University, Corso Raffaello 30, 10125 Torino, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Carabelli
authors.affiliation: Department of Drug Science and Technology, Torino University, Corso Raffaello 30, 10125 Torino, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Carbone
authors.affiliation: Department of Drug Science and Technology, Torino University, Corso Raffaello 30, 10125 Torino, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Marcantoni
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000819:agonists / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D051036:Large-Conductance Calcium-Activated Potassium Channels; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; D019837:Ryanodine Receptor Calcium Release Channel; C075222:amyloid beta-protein (1-42)
keywords: NMDA receptors; big conductance Ca2+ activated potassium (BK) channels; ryanodine receptors; spontaneous calcium transients; voltage gated Ca2+ channels