Reversible physiological alterations in sympathetic neurons deprived of NGF but protected from apoptosis by caspase inhibition or Bax deletion

Cell death in nervous system development and in many neurodegenerative dise ases appears to be apoptotic or programmed. Withdrawal of nerve growth fact or (NGF) from cultures of superior cervical ganglia neurons (SCG) is an exc ellent model of programmed cell death (PCD), producing apoptosis within 24- 48 h. This death can be prevented by treatment with caspase inhibitors or d eletion of the proapoptotic Box gene. Since inhibition of apoptosis is an a ttractive strategy for the therapy of many neurological diseases and little is known about the function of neurons when apoptosis has been aborted, we examined the electrophysiological properties of NGF-deprived SCG neurons f rom rats and mice, saved by the caspase inhibitor boc-aspartyl(OMe)fluorome thyl ketone (BAF) or by Bar deletion, Compared to NGF-maintained controls, the resting membrane potentials of BAF-saved neurons were depolarized by 9 mV and the action potentials were prolonged by over 50%, Nicotinic choliner gic current density was depressed by about 50%. Electro-physiological param eters returned to normal within 4 days after NGF restoration. Neurons from Bax-deficient mice were altered differently by NGF withdrawal. There were n o detectable changes in resting or action potentials. However, nicotinic cu rrent density was reduced just as in BAF-saved rat neurons. There were no o bservable changes in the processes of individual neurons after 6 days of NG F deprivation in the presence of BAF, Our results indicate that neurons are physiologically altered during pharmacological inhibition of PCD, but full y recover after trophic support is returned, (C) 2000 Academic Press.