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

Mariusz Popek,Joanna Sowa,Bartosz Bobula,Barbara Zabłocka,Rafał Polowy,Grzegorz Hess,Małgorzata Frontczak-Baniewicz,Magdalena Zielińska,Robert Kuba Filipkowski,Jan Albrecht

doi:10.1007/s12035-016-0367-4

Mariusz Popek, Joanna Sowa + Show 8 more

Open Access

https://doi.org/10.1007/s12035-016-0367-4

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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.

Highlights

Neuropsychiatric symptoms of acute or chronic liver failure (ALF or CLF), collectively defined as hepatic encephalopathy (HE), are associated with a decline of excitatory neurotransmission [1,2,3]
The present study provided an exhaustive description of alterations in synaptic transmission, ultrastructure, and expression of synaptic transmission-related proteins in the frontal cortex of mice with acute liver failure (ALF)
The AOM model reproduced a wide spectrum of changes in blood and brain biochemistry as well as in neurophysiological and behavioral manifestations of ALF, each reflecting those reported for acute HE in different animal ALF models [25, 32,33,34] and the health status of patients with ALF [35,36,37]

Summary

Introduction

Neuropsychiatric symptoms of acute or chronic liver failure (ALF or CLF), collectively defined as hepatic encephalopathy (HE), are associated with a decline of excitatory neurotransmission [1,2,3]. Present knowledge of the electrophysiological and molecular correlates of ALF- or CLF-affected synapse is confined mostly to the postsynaptic events related to altered Glu receptor-mediated signaling pathways [4] and/or synaptic plasticity, i.e., long-term potentiation (LTP) and LTD [5], while the status of the presynaptic region involved in neurotransmitter release has remained unattended. We address the question whether and to what extent ALF disturbs the functional and structural integrity of the presynaptic neurotransmitter release machinery in addition to postsynaptic changes.

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