Synaptic activity becomes excitotoxic in neurons exposed to elevated levels of platelet-activating factor.
Neurologic impairment in HIV-1-associated dementia (HAD) and other neuroinflammatory diseases correlates with injury to dendrites and synapses, but how such injury occurs is not known. We hypothesized that neuroinflammation makes dendrites susceptible to excitotoxic injury following synaptic activity. We report that platelet-activating factor, an inflammatory phospholipid that mediates synaptic plasticity and neurotoxicity and is dramatically elevated in the brain during HAD, promotes dendrite injury following elevated synaptic activity and can replicate HIV-1-associated dendritic pathology. In hippocampal slices exposed to a stable platelet-activating factor analogue, tetanic stimulation that normally induces long-term synaptic potentiation instead promoted development of calcium- and caspase-dependent dendritic beading. Chemical preconditioning with diazoxide, a mitochondrial ATP-sensitive potassium channel agonist, prevented dendritic beading and restored long-term potentiation. In contrast to models invoking excessive glutamate release, these results suggest that physiologic synaptic activity may trigger excitotoxic dendritic injury during chronic neuroinflammation. Furthermore, preconditioning may represent a novel therapeutic strategy for preventing excitotoxic injury while preserving physiologic plasticity.
Bellizzi
Matthew J
MJ
Department of Neurology, Child Neurology Division, Center for Aging and Developmental Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA. matthew_bellizzi@urmc.rochester.edu
Lu
Shao-Ming
SM
Masliah
Eliezer
E
Gelbard
Harris A
HA
D015526:AIDS Dementia Complex / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002118:Calcium / Q000502:physiology; D020169:Caspases / Q000502:physiology; D049229:Dendritic Spines / Q000187:drug effects / Q000473:pathology*; D004558:Electric Stimulation; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D006801:Humans; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D009924:Organ Culture Techniques; D010477:Perfusion; D010742:Phospholipid Ethers / Q000633:toxicity; D010972:Platelet Activating Factor / Q000819:agonists / Q000031:analogs & derivatives / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
D010742:Phospholipid Ethers; D010972:Platelet Activating Factor; C053479:1-O-hexadecyl-2-N-methylcarbamylphosphatidylcholine; D020169:Caspases; D002118:Calcium