Homeostatic effects of depolarization on Ca²⁺ influx, synaptic signaling, and survival

Depolarization promotes neuronal survival through moderate increases in Ca²⁺ influx, but the effects of survival-promoting depolarization (vs conventional trophic support) on neuronal signaling are poorly characterized. We found that chronic, survival-promoting depolarization, but not conventional trophic support, selectively decreased the somatic Ca²⁺ current density in hippocampal and cerebellar granule neurons. Depolarization rearing depressed multiple classes of high-voltage activated Ca²⁺ current. Consistent with the idea that these changes also affected synaptic Ca²⁺ channels, chronic depolarization presynaptically depressed hippocampal neurotransmission. Six days of depolarization rearing completely abolished glutamate transmission but altered GABA transmission in a manner consistent with the alterations of Ca²⁺ current. The continued survival of depolarization-reared neurons was extremely sensitive to the re-establishment of basal culture conditions and was correlated with the effects on intracellular Ca²⁺ concentration. Thus, compared with cells reared on conventional trophic factors, depolarization evokes homeostatic changes in Ca²⁺ influx and signaling that render neurons vulnerable to cell death on activity reduction.