Cortical Synaptic Transmission and Plasticity in Acute Liver Failure Are Decreased by Presynaptic Events.

Popek M1, Bobula B2, Sowa J2, Hess G2, Polowy R3, Filipkowski RK3, Frontczak-Baniewicz M4, Zabłocka B5, Albrecht J1, Zielińska M6.

Cortical Synaptic Transmission and Plasticity in Acute Liver Failure Are Decreased by Presynaptic Events.

Author information:

1 Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 St, 02-106, Warsaw, Poland.

2 Department of Physiology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12 St, 31-343, Cracow, Poland.

3 Behavior and Metabolism Research Laboratory, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 St, 02-106, Warsaw, Poland.

4 Electron Microscopy Platform, Mossakowski Medical Research Centre Polish Academy of Sciences, Pawińskiego 5 St, 02-106, Warsaw, Poland.

5 Molecular Biology Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 St, 02-106, Warsaw, Poland.

6 Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 St, 02-106, Warsaw, Poland. Ten adres pocztowy jest chroniony przed spamowaniem. Aby go zobaczyć, konieczne jest włączenie w przeglądarce obsługi JavaScript..

 

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.

KEYWORDS:

Acute liver failure; Neurotransmission; Presynaptic events

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