Synaptic activity becomes excitotoxic in neurons exposed to elevated levels of platelet-activating factor

J Clin Invest. 2005 Nov;115(11):3185-92. doi: 10.1172/JCI25444.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • AIDS Dementia Complex / metabolism
  • AIDS Dementia Complex / pathology
  • Animals
  • Calcium / physiology
  • Caspases / physiology
  • Dendritic Spines / drug effects
  • Dendritic Spines / pathology*
  • Electric Stimulation
  • Hippocampus / drug effects
  • Hippocampus / pathology
  • Humans
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / physiology
  • Male
  • Neurons / drug effects
  • Neurons / pathology*
  • Organ Culture Techniques
  • Perfusion
  • Phospholipid Ethers / toxicity
  • Platelet Activating Factor / agonists
  • Platelet Activating Factor / analogs & derivatives
  • Platelet Activating Factor / toxicity*
  • Rats
  • Rats, Sprague-Dawley
  • Synaptic Transmission / drug effects*
  • Synaptic Transmission / physiology


  • Phospholipid Ethers
  • Platelet Activating Factor
  • 1-O-hexadecyl-2-N-methylcarbamylphosphatidylcholine
  • Caspases
  • Calcium