Calbindin overexpression buffers hippocampal cultures from the energetic impairments caused by glutamate

A dramatic rise in free cytosolic calcium concentration is thought to be a central event in the pathogenesis of glutamate excitotoxicity in neurons. We have previously demonstrated that gene transfer of the calcium-binding protein calbindin D28k via a Herpes simplex amplicon vector decreases the rise in intracellular calcium and promotes cell survival following glutamatergic challenge. This study explores the effect of calbindin transgene expression on cellular metabolism following glutamate excitotoxicity. Because excitotoxic insults are often energetic in nature, and because calcium sequestering and extrusion place heavy energy demands on a cell, we hypothesized that calbindin overexpression may help preserve cellular energy levels during an insult. We overexpressed calbindin in primary hippocampal cultures, using a Herpes simplex amplicon vector system. We found that calbindin overexpression protected neurons from the decline in ATP levels, mitochondrial potential and metabolic rate following a glutamatergic insult. These results indicate that calbindin expression helps preserve cellular energy state following glutamate excitotoxicity. This illustrates the energetic load placed on neurons by increased free cytosolic calcium and may help explain the neuroprotective effects of calbindin.