Trophic Support of Cultured Spiral Ganglion Neurons by Depolarization Exceeds and Is Additive with that by Neurotrophins or cAMP and Requires Elevation of [Ca2+]iwithin a Set Range

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Abstract
Spiral ganglion neurons (SGNs) require both pre- and postsynaptic contacts to maintain viability. BDNF, NT-3, chlorphenylthio-cAMP, and depolarization (veratridine or elevated [K+]o) all promote survival of SGNsin vitro, depolarization being the most effective. Combining different trophic stimuli increases survival in an additive manner. Neurotrophins and depolarization maintain comparable soma size and neurite extension, but SGNs are shrunken in cAMP. Elevated [K+]ohas a biphasic effect on SGN survival; survival improves as [K+]ois raised to 30 mm(30K) and falls as [K+]ois further increased; SGN survival in 80 mm[K+]o(80K) is poor relative to survival in 30K. These responses to elevated [K+]oare potentiated by an L-type channel agonist, whereas L-type Ca2+channel blockers antagonize the trophic effect of depolarization. Four hours after depolarization, steady-state [Ca2+]iis elevated in SGNs in 30K and further elevated in SGNs in 80K. At 22 hr after depolarization, by which time death of neurons in 80K has begun, elevated [Ca2+]ilevels in surviving neurons in 80K are not higher than those in neurons in 30K (∼150–450 nm), suggesting that neurons with high [Ca2+]iare preferentially lost. Veratridine causes oscillatory increases in [Ca2+]ito 250–350 nm. Thus, [Ca2+]iis predictive of cell survival; [Ca2+]ielevated to 100–500 nmin a sustained or oscillatory manner permits SGN survival independent of exogenous neurotrophic factors. Higher [Ca2+]iis associated with cell death.