Caffeine Releasable Stores of Ca Show Depletion Prior to the Final Steps in Delayed CA1 Neuronal Death

Xing, Hong, Aryan Azimi-Zonooz, C. William Shuttleworth, and John A. Connor. Caffeine releasable stores of Ca show depletion prior to the final steps in delayed CA1 neuronal death. J Neurophysiol 92: 2960–2967, 2004. First published June 16, 2004; 10.1152/ jn.00015.2004. In addition to their role in signaling, Ca ions in the endoplasmic reticulum also regulate important steps in protein processing and trafficking that are critical for normal cell function. Chronic depletion of Ca in the endoplasmic reticulum has been shown to lead to cell degeneration and has been proposed as a mechanism underlying delayed neuronal death following ischemic insults to the CNS. Experiments here have assessed the relative content of ryanodine receptor-gated stores in CA1 neurons by measuring cytoplasmic Ca increases induced by caffeine. These measurements were performed on CA1 neurons, in slice, from normal gerbils, and compared with responses from this same population of neurons 54–60 h after animals had undergone a standard ischemic insult: 5-min bilateral occlusion of the carotid arteries. The mean amplitude of responses in the postischemic population were less than one-third of those in control or sham-operated animals, and 35% of the neurons from postischemic animals showed very small responses that were 10% of the control population mean. Refilling of these stores after caffeine challenges was also impaired in postischemic neurons. These observations are consistent with our earlier finding that voltage-gated influx is sharply reduced in postischemic in CA1 neurons and the hypothesis that the resulting depletion in endosomal Ca is an important cause of delayed neuronal death.