title: Ammonium chloride influences in vitro-neuronal network activity.
abstract: The objective of the present work is to image functional alterations in hepatic encephalopathy (HE) by ammonia-induced changes of in vitro-neuronal network activity and to identify counteracting strategies. Synchronous bursting behavior of rat cortical cells which is the result of synaptic interaction of excitatory and inhibitory neurons was recorded in vitro on microelectrode arrays (MEAs) after ammonium chloride exposure. In order to test the involvement of astrocytic glutamine metabolism and N-methyl-d-aspartic acid- (NMDA-) receptor function in the observed ammonia-induced network dysregulation and to identify potentially protective strategies, we investigated effects of the glutamine synthetase (GS) inhibitor methionine-sulfoximine (MSO) and the NMDA-receptor antagonist DL-2-Amino-5-phosphono-pentanoic acid (AP-5), respectively. We observed a characteristic ammonia-induced increase of global network activity while network synchrony was suppressed. The increase of global activity, but not the suppression of network synchrony was prevented by inhibiting GS. However, blocking NMDA-receptors prevented both, network excitation and desynchronization.
  
  
  CONCLUSIONS
  1. The observed desynchronization of in vitro-neuronal network activity after ammonium chloride treatment might reflect global neuronal network changes in HE in vivo and suggests the MEA technology as a valuable tool for measuring changes of neuronal connectivity in vitro. 2. Astrocytic glutamine metabolism might be involved in increased global network activity, but not in the suppression of network synchrony. 3. Overactivation of NMDA-receptors might underlie both, the ammonia-induced increase of activity and suppression of network synchrony, suggesting that NMDA-receptor function is involved in HE and that their blockage might be protective. 4. Measuring neuronal network activity in vitro by the MEA technology might help to describe functionally protective measures in HE.
authors.affiliation: Department of Neurology, Heinrich-Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany. clara-sophie.schwarz@uni-duesseldorf.de
authors.forename: Clara-Sophie
authors.initials: CS
authors.lastname: Schwarz
authors.forename: Stefano
authors.initials: S
authors.lastname: Ferrea
authors.forename: Kim
authors.initials: K
authors.lastname: Quasthoff
authors.forename: Janine
authors.initials: J
authors.lastname: Walter
authors.forename: Boris
authors.initials: B
authors.lastname: Görg
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
authors.forename: Alfons
authors.initials: A
authors.lastname: Schnitzler
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hartung
authors.forename: Marcel
authors.initials: M
authors.lastname: Dihné
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000643:Ammonium Chloride / Q000494:pharmacology*; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D008717:Methionine Sulfoximine / Q000494:pharmacology; D009415:Nerve Net / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D000643:Ammonium Chloride; D005973:Glutamine; D008717:Methionine Sulfoximine; D015763:2-Amino-5-phosphonovalerate; D005974:Glutamate-Ammonia Ligase