In addition to their role in signaling, Ca²⁺ ions in the endoplasmic reticulum also regulate important steps in protein processing and trafficking that are critical for normal cell function. Chronic depletion of Ca²⁺ 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 Ca²⁺ 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 hr after animals had undergone a standard ischemic insult, 5 min bilateral occlusion of the carotid arteries. The mean amplitude of responses in the post-ischemic population were < 1/3 of those in control or sham-operated animals and 35% of the neurons from post-ischemic animals showed very small responses that were ~10% of the control population mean. Refilling of these stores after caffeine challenges was also impaired in post-ischemic neurons. These observations are consistent with our earlier finding that voltage-gated influx is sharply reduced in post-ischemic in CA1 neurons and the hypothesis that the resulting depletion in endosomal Ca²⁺ is an important cause of delayed neuronal death.