title: Depletion of the AMPAR reserve pool impairs synaptic plasticity in a model of hepatic encephalopathy.
abstract: Hepatic encephalopathy (HE) is the most common neuropsychiatric complication of acute or chronic liver failure. Clinical symptoms include cognitive and intellectual dysfunction as well as impaired motor activity and coordination. There is general consensus that increased levels of ammonia play a central role in the pathogenesis of HE. However, it is still elusive how cognitive performance including the ability to learn and memorize information is affected by ammonia at molecular levels. In the present study, we have employed a neuroglial co-culture model, which preserves neuroglial interplay but allows for cell-type specific molecular and functional analyses, to investigate glutamatergic neurotransmission under conditions of high ammonia. Chronic exposure to ammonia significantly reduced neuronal mRNA and protein expression of AMPA-subtype glutamate receptors (AMPARs), which mediate most fast excitatory neurotransmission in the brain. Surprisingly, neurons were able to fully maintain basal glutamatergic neurotransmission as recorded by AMPAR-mediated miniature excitatory postsynaptic currents (mEPSCs) even when >50% of total AMPARs were lost. However, long-lasting, activity-dependent changes in the efficacy of synaptic communication, which model the capability of the brain to learn and store information, were severely constrained. Whereas synaptic efficacy could still be depressed, an increase in synaptic strength was abolished. We conclude that neurons retain basal glutamatergic transmission at the expense of the extrasynaptic population of AMPARs, which is revealed when the extrasynaptic reserve pool is recruited in vain for synaptic potentiation. Our findings thus offer a molecular model, which might not only explain impaired synaptic plasticity in HE but also in other neurological diseases accompanied by a decrease in extrasynaptic AMPAR expression.
authors.affiliation: Institute of Neural and Sensory Physiology, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Annett
authors.initials: A
authors.lastname: Schroeter
authors.affiliation: Institute of Neural and Sensory Physiology, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Shuping
authors.initials: S
authors.lastname: Wen
authors.affiliation: Institute of Neural and Sensory Physiology, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mölders
authors.affiliation: Institute of Neural and Sensory Physiology, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Erlenhardt
authors.affiliation: Institute of Physiology II, University of Bonn, Bonn, Germany.
authors.forename: Valentin
authors.initials: V
authors.lastname: Stein
authors.affiliation: Institute of Neural and Sensory Physiology, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany. Electronic address: nikolaj.kloecker@uni-duesseldorf.de.
authors.forename: Nikolaj
authors.initials: N
authors.lastname: Klöcker
mesh_terms: D000641:Ammonia / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D015220:Calcium Channels / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: C491911:Cacng2 protein, rat; D015220:Calcium Channels; D018690:Excitatory Amino Acid Agonists; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D018091:Receptors, AMPA; D016202:N-Methylaspartate; D000641:Ammonia; D007770:L-Lactate Dehydrogenase
keywords: AMPA receptor; Ammonia; Glutamatergic neurotransmission; Hepatic encephalopathy; LTD; LTP; NMDA receptor; Neuroglial co-culture