Evidence for a role for the group I metabotropic glutamate receptor in the inhibitory effect of tumor necrosis factor-alpha on long-term potentiation.
Pro-inflammatory cytokines are known to be elevated in several neuropathological states that are associated with learning and memory. We have previously demonstrated in our laboratory that the inhibition of long-term potentiation (LTP) in the dentate gyrus region of the rat hippocampus, by tumor necrosis factor (TNF)-alpha, represents a biphasic response, an early phase dependent on p38 mitogen activated protein kinase (MAPK) activation and a later phase, possible dependent on protein synthesis. Many of the factors involved in the early modulation of LTP by TNF-alpha have yet to be elucidated. This study investigated if metabotropic glutamate receptors (mGluRs) are functionally linked to the inhibitory effect of TNF-alpha on LTP in the rat dentate gyrus in vitro. We report that the impairment of early-LTP by TNF-alpha is significantly attenuated by prior application of the group I/II mGluR antagonist MCPG and more specifically the mGluR5 antagonist MPEP. Since TNF-alpha is now known to cause transient increases in intracellular Ca(2+) levels from ryanodine-sensitive stores, we explored the possibility that disruption of intracellular Ca(2+) homeostasis could be involved. Ryanodine was found to significantly reverse the inhibition of LTP by TNF-alpha. From these studies we propose that the TNF-alpha inhibition of LTP is dependent upon the activation of TNFR1 and mGlu5-receptors. Importantly this study provides the first proof of the involvement of ryanodine-sensitive intracellular Ca(2+) stores in TNF-alpha mediated inhibition of LTP.
Cumiskey
D
D
UCD School of Biomolecular and Biomedical Science, UCD Conway Institute of Biomolecular and Biomedical Research, Belfield, Dublin 4, Ireland.
Butler
M P
MP
Moynagh
P N
PN
O'connor
J J
JJ
D000818:Animals; D018891:Dentate Gyrus / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000528:radiation effects; D008297:Male; D008954:Models, Biological; D009433:Neural Inhibition / Q000187:drug effects*; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D012433:Ryanodine / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; D014409:Tumor Necrosis Factor-alpha; C104077:metabotropic glutamate receptor type 1; D012433:Ryanodine