EVIDENCE THAT ACTIN DEPOLYMERIZATION PROTECTS HIPPOCAMPAL-NEURONS AGAINST EXCITOTOXICITY BY STABILIZING [CA2+]I

Calcium influx through glutamate receptors and voltage-dependent chann els mediates an array of functional and structural responses in neuron s. However, unrestrained Ca2+ influx can injure and kill neurons; a me chanism implicated in both acute and chronic neurodegenerative disorde rs. Data reported here indicate that depolymerization of actin filamen ts can stabilize intracellular free calcium levels ([Ca2+](i)) and pro tect hippocampal neurons against excitotoxic injury. Studies with fluo rescein-labeled phalloidin showed that cytochalasin D and glutamate ea ch induced actin filament depolymerization. The microfilament-disrupti ng agent cytochalasin D protected cultured rat hippocampal neurons aga inst glutamate toxicity, whereas the actin filament-stabilizing agent jasplakinolide potentiated glutamate toxicity. The microtubule-disrupt ing agent colchicine was ineffective in protecting neurons against glu tamate toxicity. Cytochalasin D did not protect neurons against calciu m ionophore toxicity or iron toxicity, indicating that its actions wer e not due to nonspecific effects on Ca2+ or free radical metabolism. C ytochalasin D markedly attenuated kainate-induced damage to hippocampu s of adult rats, suggesting an excitoprotective role for actin depolym erization in vivo. Elevations of [Ca2+](i) induced by glutamate were a ttenuated 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, s uggesting that actin depolymerization reduced Ca2+ influx through memb rane channels. Taken together with previous patch clamp data, our find ings suggest that depolymerization of actin in response to Ca2+ influx may serve as a feedback mechanism to attenuate potentially toxic leve ls of Ca2+ influx. (C) 1995 Academic Press, Inc.