Evidence that actin depolymerization protects hippocampal neurons against excitotoxicity by stabilizing [Ca2+]i

Exp Neurol. 1995 Jun;133(2):153-63. doi: 10.1006/exnr.1995.1018.


Calcium influx through glutamate receptors and voltage-dependent channels mediates an array of functional and structural responses in neurons. However, unrestrained Ca2+ influx can injure and kill neurons; a mechanism implicated in both acute and chronic neurodegenerative disorders. Data reported here indicate that depolymerization of actin filaments can stabilize intracellular free calcium levels ([Ca2+]i) and protect hippocampal neurons against excitotoxic injury. Studies with fluorescein-labeled phalloidin showed that cytochalasin D and glutamate each induced actin filament depolymerization. The microfilament-disrupting agent cytochalasin D protected cultured rat hippocampal neurons against glutamate toxicity, whereas the actin filament-stabilizing agent jasplakinolide potentiated glutamate toxicity. The microtubule-disrupting agent colchicine was ineffective in protecting neurons against glutamate toxicity. Cytochalasin D did not protect neurons against calcium ionophore toxicity or iron toxicity, indicating that its actions were not due to nonspecific effects on Ca2+ or free radical metabolism. Cytochalasin D markedly attenuated kainate-induced damage to hippocampus of adult rats, suggesting an excitoprotective role for actin depolymerization in vivo. Elevations of [Ca2+]i induced by glutamate were attenuated in cultured hippocampal neurons pretreated with cytochalasin D and potentiated in neurons pretreated with jasplakinolide. The [Ca2+]i response to a Ca2+ ionophore was unaffected by cytochalasin D, suggesting that actin depolymerization reduced Ca2+ influx through membrane channels. Taken together with previous patch clamp data, our findings suggest that depolymerization of actin in response to Ca2+ influx may serve as a feedback mechanism to attenuate potentially toxic levels of Ca2+ influx.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actins / metabolism*
  • Animals
  • Calcium / metabolism*
  • Cells, Cultured
  • Cytochalasins / pharmacology
  • Depsipeptides*
  • Drug Synergism
  • Glutamic Acid / pharmacology
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Intracellular Membranes / metabolism
  • Male
  • Neurons / drug effects*
  • Neuroprotective Agents / pharmacology
  • Neurotoxins / pharmacology*
  • Osmolar Concentration
  • Peptides, Cyclic / pharmacology
  • Polymers / metabolism*
  • Rats
  • Rats, Sprague-Dawley


  • Actins
  • Cytochalasins
  • Depsipeptides
  • Neuroprotective Agents
  • Neurotoxins
  • Peptides, Cyclic
  • Polymers
  • jasplakinolide
  • Glutamic Acid
  • Calcium