title: Homeostatic presynaptic suppression of neuronal network bursts.
abstract: Spontaneous synchronized bursts of activity play an essential role in the maturation and plasticity of neuronal networks. To investigate the cellular properties that enable spontaneous network activity, we used dissociated cultures of hippocampal neurons that express prolonged network activity bursts. Acute exposure to a low concentration of N-methyl-d-aspartate (NMDA) caused an increase in spontaneous firing rates and intracellular calcium concentration ([Ca(2+)]i). However, in the course of a chronic (>1 day) exposure to NMDA, [Ca(2+)]i recovered back to normal baseline levels, and only sporadic asynchronous calcium transients were detected. Spontaneous network bursts were still absent 1 h after the removal of NMDA, indicating a persistent downregulation of network activity, which did recover eventually 2 days later. This effect of NMDA was activity-dependent as it was blocked by co-application of tetrodotoxin (TTX). The chronic NMDA-treated neurons expressed normal morphology and active membrane properties as well as spontaneous miniature excitatory postsynaptic currents and postsynaptic reactivity to glutamate. However, in response to trains of afferent stimulation in paired recordings, the treated neurons expressed synaptic depression as opposed to synaptic potentiation seen in control cells. Also, treated neurons did not respond to low-intensity electrical field stimulation as did control cells. Finally, Western blot analysis revealed that chronic exposure to NMDA altered presynaptic but not postsynaptic protein expression patterns, suggesting a presynaptic locus of effect. Thus a long-lasting increase in activity downregulates neurotransmitter release to prevent over-excitation of the network and, consequently, blocks the generation of network bursts.
authors.affiliation: Dept. of Neurobiology, The Weizmann Institute, Rehovot 76100, Israel.
authors.forename: Dror
authors.initials: D
authors.lastname: Cohen
authors.forename: Menahem
authors.initials: M
authors.lastname: Segal
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D004622:Embryo, Mammalian; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D008012:Lidocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D009415:Nerve Net / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D050988:Vesicle-Associated Membrane Protein 2 / Q000378:metabolism
chemical_list: D000779:Anesthetics, Local; D002118:Calcium; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D049452:Green Fluorescent Proteins; D008012:Lidocaine; D016202:N-Methylaspartate; D011810:Quinoxalines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D050825:Synaptosomal-Associated Protein 25; D013779:Tetrodotoxin; D014633:Valine; D050988:Vesicle-Associated Membrane Protein 2; C409466:NR1 NMDA receptor; C494210:Snap25 protein, rat; C012647:QX-314; C056723:FG 9041; C056639:2-amino-5-phosphopentanoic acid