In vitro aging promotes endoplasmic reticulum (ER)-mitochondria Ca(2+) cross talk and loss of store-operated Ca(2+) entry (SOCE) in rat hippocampal neurons.

Aging is associated to cognitive decline and susceptibility to neuron death, two processes related recently to subcellular Ca(2+) homeostasis. Memory storage relies on mushroom spines stability that depends on store-operated Ca(2+) entry (SOCE). In addition, Ca(2+) transfer from endoplasmic reticulum (ER) to mitochondria sustains energy production but mitochondrial Ca(2+) overload promotes apoptosis. We have addressed whether SOCE and ER-mitochondria Ca(2+) transfer are influenced by culture time in long-term cultures of rat hippocampal neurons, a model of neuronal aging. We found that short-term cultured neurons show large SOCE, low Ca(2+) store content and no functional coupling between ER and mitochondria. In contrast, in long-term cultures reflecting aging neurons, SOCE is essentially lost, Stim1 and Orai1 are downregulated, Ca(2+) stores become overloaded, Ca(2+) release is enhanced, expression of the mitochondrial Ca(2+) uniporter (MCU) increases and most Ca(2+) released from the ER is transferred to mitochondria. These results suggest that neuronal aging is associated to increased ER-mitochondrial cross talking and loss of SOCE. This subcellular Ca(2+) remodeling might contribute to cognitive decline and susceptibility to neuron cell death in the elderly.