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 activit...

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Bibliographic Details
Published in:The Journal of clinical investigation 2005-11, Vol.115 (11), p.3185-3192
Main Authors: Bellizzi, Matthew J, Lu, Shao-Ming, Masliah, Eliezer, Gelbard, Harris A
Format: Article
Language:English
Subjects:
AIDS Dementia Complex - metabolism
AIDS Dementia Complex - pathology
Animals
Biomedical research
Calcium - physiology
Caspases - physiology
Dementia
Dendritic Spines - drug effects
Dendritic Spines - pathology
Disease
Electric Stimulation
Hippocampus - drug effects
Hippocampus - pathology
Humans
Long-Term Potentiation - drug effects
Long-Term Potentiation - physiology
Male
Neurons
Neurons - drug effects
Neurons - pathology
Neurotoxicity
Organ Culture Techniques
Pathology
Perfusion
Phospholipid Ethers - toxicity
Platelet Activating Factor - agonists
Platelet Activating Factor - analogs & derivatives
Platelet Activating Factor - toxicity
Potassium
Rats
Rats, Sprague-Dawley
Synaptic Transmission - drug effects
Synaptic Transmission - physiology
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Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI25444