Homeostatic Effects of Depolarization on Ca²⁺Influx, Synaptic Signaling, and Survival

Abstract

Depolarization promotes neuronal survival through moderate increases in Ca(2+) 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 Ca(2+) current density in hippocampal and cerebellar granule neurons. Depolarization rearing depressed multiple classes of high-voltage activated Ca(2+) current. Consistent with the idea that these changes also affected synaptic Ca(2+) 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 Ca(2+) 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 Ca(2+) concentration. Thus, compared with cells reared on conventional trophic factors, depolarization evokes homeostatic changes in Ca(2+) influx and signaling that render neurons vulnerable to cell death on activity reduction.

Decreased Synaptic Activity Shifts the Calcium Dependence of Release at the Mammalian Neuromuscular JunctionIn Vivo

“…Our data, as well as previous studies (Tsujimoto et al, 1990;Lnenicka and Hong, 1997;Murthy et al, 2001;Paradis et al, 2001;Moulder et al, 2003), suggest that homeostatic regulation of quantal content occurs because of regulation of probability of release. If homeostatic regulation of synaptic strength is mediated through increases in probability of release rather than increases in the number of synaptic sites, two predictions follow.…”

“…It has been proposed that CaMKII (calcium/calmodulindependent protein kinase II) signaling is involved in the activitydependent regulation of quantal size and the number of functional synaptic sites (Thiagarajan et al, 2002;Haghighi et al, 2003;Pratt et al, 2003). Our data as well as previous studies (Lnenicka and Hong, 1997;Moulder et al, 2003) suggest that signals that regulate Ca 2ϩ channel isoform expression or function (Atwood and Karunanithi, 2002;Weiss and Burgoyne, 2002;Reid et al, 2003) may be involved in activity-dependent regulation of synaptic function.…”

“…As reported in this study, block of P/Q channels eliminated the difference in probability of release. At synapses between neurons in vitro, there is evidence that chronic depolarization of neurons (perhaps mimicking increased activity) reduces probability of release by reducing presynaptic calcium currents (Moulder et al, 2003). Work at the crayfish neuromuscular junction has shown that increased activity produces weakening of synaptic strength that lasts for days to weeks Atwood, 1985, 1989).…”

A Specific Role for Ca2+-Dependent Adenylyl Cyclases in Recovery from Adaptive Presynaptic Silencing

“…Because depolarization-induced presynaptic silencing has been fairly thoroughly characterized in our previous studies, unsilencing appears well poised for additional investigation (Moulder et al, 2003(Moulder et al, , 2004(Moulder et al, , 2006. Hallmarks of silencing include the inability of silenced terminals to release transmitter, even in response to the Ca 2ϩ -independent secretagogue hypertonic sucrose.…”

Why photoreceptors die (and why they don't)

“…(51) Considerable experimentation indicates that the elevated K þ has its effect by depolarizing the cells and opening voltage-gated Ca 2þ channels, producing an increase in the intracellular free Ca 2þ concentration. (52)(53)(54)(55)(56)(57) The evident conclusion is that the cells in normal K þ are dying because the Ca 2þ concentration is too low (see also Refs. 58 and 59).…”