title: Activity-dependent augmentation of spontaneous neurotransmission during endoplasmic reticulum stress.
abstract: The endoplasmic reticulum (ER) is an essential cellular compartment responsible for Ca(2+) sequestration, signaling, protein translation, folding as well as transport. Several acute and chronic disease conditions impair ER function leading to ER stress. To study the impact of ER stress on synaptic transmission we applied tunicamycin (TM) or thapsigargin (TG) to hippocampal neurons, which triggered sustained elevation of key ER stress markers. We monitored evoked and spontaneous neurotransmission during 4 d of TM or TG treatment and detected only a 20% increase in paired pulse depression suggesting an increase in neurotransmitter release probability. However, the treatments did not significantly affect the number of active synapses or the size of the total recycling vesicle pool as measured by uptake and release of styryl dye FM1-43. In contrast, under the same conditions, we observed a dramatic fourfold increase in spontaneous excitatory transmission, which could be reversed by chronic treatment with the NMDA receptor blocker AP-5 or by treatment with salubrinal, a selective inhibitor of eukaryotic translation initiation factor 2 (eIF2alpha) dephosphorylation. Furthermore, ER stress caused NMDA receptor-dependent suppression of eukaryotic elongation factor-2 (eEF2) phosphorylation thus reversing downstream signaling mediated by spontaneous release. Together, these findings suggest that chronic ER stress augments spontaneous excitatory neurotransmission and reverses its downstream signaling in a NMDA receptor-dependent manner, which may contribute to neuronal circuitry abnormalities that precede synapse degeneration in several neurological disorders.
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Nosyreva
authors.forename: Ege T
authors.initials: ET
authors.lastname: Kavalali
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure*; D018408:Patch-Clamp Techniques / Q000379:methods; D010766:Phosphorylation; D010852:Picrotoxin / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D015763:2-Amino-5-phosphonovalerate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D002118:Calcium; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D010852:Picrotoxin; D011726:Pyridinium Compounds; D000644:Quaternary Ammonium Compounds; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D019284:Thapsigargin; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D014415:Tunicamycin; C497250:Ddit3 protein, mouse; C103652:Elf2 protein, mouse; C073804:FM1 43