TY - JOUR
T1 - Activity-dependent augmentation of spontaneous neurotransmission during endoplasmic reticulum stress
AU - Nosyreva, Elena
AU - Kavalali, Ege T.
PY - 2010/5/26
Y1 - 2010/5/26
N2 - The endoplasmic reticulum (ER) is an essential cellular compartment responsible for Ca2+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 TMor TGtreatment 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 (eIF2α) dephosphorylation. Furthermore, ER stress caused NMDAreceptor-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. Copyright
AB - The endoplasmic reticulum (ER) is an essential cellular compartment responsible for Ca2+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 TMor TGtreatment 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 (eIF2α) dephosphorylation. Furthermore, ER stress caused NMDAreceptor-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. Copyright
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U2 - 10.1523/JNEUROSCI.5358-09.2010
DO - 10.1523/JNEUROSCI.5358-09.2010
M3 - Article
C2 - 20505103
AN - SCOPUS:77953037772
SN - 0270-6474
VL - 30
SP - 7358
EP - 7368
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 21
ER -