title: Cortical Synaptic Transmission and Plasticity in Acute Liver Failure Are Decreased by Presynaptic Events.
abstract: Neurological symptoms of acute liver failure (ALF) reflect decreased excitatory transmission, but the status of ALF-affected excitatory synapse has not been characterized in detail. We studied the effects of ALF in mouse on synaptic transmission and plasticity ex vivo and its relation to distribution of (i) synaptic vesicles (sv) and (ii) functional synaptic proteins within the synapse. ALF-competent neurological and biochemical changes were induced in mice with azoxymethane (AOM). Electrophysiological characteristics (long-term potentiation, whole-cell recording) as well as synapse ultrastructure were evaluated in the cerebral cortex. Also, sv were quantified in the presynaptic zone by electron microscopy. Finally, presynaptic proteins in the membrane-enriched (P2) and cytosolic (S2) fractions of cortical homogenates were quantitated by Western blot. Slices derived from symptomatic AOM mice presented a set of electrophysiological correlates of impaired transmitter release including decreased field potentials (FPs), increased paired-pulse facilitation (PPF), and decreased frequency of spontaneous and miniature excitatory postsynaptic currents (sEPSCs/mEPSCs) accompanied by reduction of the spontaneous transmitter release-driving protein, vti1A. Additionally, an increased number of sv per synapse and a decrease of P2 content and/or P2/S2 ratio for sv-associated proteins, i.e. synaptophysin, synaptotagmin, and Munc18-1, were found, in spite of decreased content of the sv-docking protein, syntaxin-1. Slices from AOM-treated asymptomatic mice showed impaired long-term potentiation (LTP) and increased PPF but no changes in transmitter release or presynaptic protein composition. Our findings demonstrate that a decrease of synaptic transmission in symptomatic ALF is associated with inefficient recruitment of sv proteins and/or impaired sv trafficking to transmitter release sites.
authors.affiliation: Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 St, 02-106, Warsaw, Poland.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Popek
authors.affiliation: Department of Physiology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12 St, 31-343, Cracow, Poland.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Bobula
authors.affiliation: Department of Physiology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12 St, 31-343, Cracow, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Sowa
authors.affiliation: Department of Physiology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12 St, 31-343, Cracow, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Hess
authors.affiliation: Behavior and Metabolism Research Laboratory, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 St, 02-106, Warsaw, Poland.
authors.forename: Rafał
authors.initials: R
authors.lastname: Polowy
authors.affiliation: Behavior and Metabolism Research Laboratory, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 St, 02-106, Warsaw, Poland.
authors.forename: Robert Kuba
authors.initials: RK
authors.lastname: Filipkowski
authors.affiliation: Electron Microscopy Platform, Mossakowski Medical Research Centre Polish Academy of Sciences, Pawińskiego 5 St, 02-106, Warsaw, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Frontczak-Baniewicz
authors.affiliation: Molecular Biology Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 St, 02-106, Warsaw, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Zabłocka
authors.affiliation: Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 St, 02-106, Warsaw, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Albrecht
authors.affiliation: Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 St, 02-106, Warsaw, Poland. mzielinska@imdik.pan.pl.
authors.forename: Magdalena
authors.identifier: 0000-0001-7388-3092
authors.initials: M
authors.lastname: Zielińska
mesh_terms: D000641:Ammonia / Q000097:blood; D000818:Animals; D002540:Cerebral Cortex / Q000503:physiopathology*; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D017114:Liver Failure, Acute / Q000097:blood / Q000503:physiopathology*; D008297:Male; D051379:Mice; D009473:Neuronal Plasticity / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000502:physiology*; D013569:Synapses; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D016207:Cytokines; D000641:Ammonia
keywords: Acute liver failure; Neurotransmission; Presynaptic events