Biology Reference
In-Depth Information
4.1. Depolarization
Scott and Fisher (1970
) showed that maintaining chicken dorsal root gan-
glion cells in a culture medium containing elevated concentrations of K
þ
significantly enhanced their survival rates (
Scott & Fisher, 1970
). Because
high extracellular K
þ
concentrations ([K
þ
]) promoted the
in vitro
survival
of many other types of neurons (
Franklin, & Johnson, 1992
), the increased
[K
þ
] probably enhanced the survival by causing a chronic depolarization of
the neurons that mimic the effects of natural electrical activity. Sustained de-
polarization apparently induced prolonged activation of voltage-gated Ca
2
þ
channels (
Collins & Lile, 1989; Nishi & Berg, 1981
). The influx of Ca
2
þ
through these channels has been reported to cause a sustained increase of
intracellular-free Ca
2
þ
concentration that is thought to mediate the effects
of the depolarization on survival (
Collins, Schmidt, Guthrie, & Kater, 1991;
Koike & Tanaka, 1991
). Voltage-gated Ca
2
þ
influx can activate the Ras/
MAPK pathway which plays important roles in neuronal survival, differen-
tiation, and plasticity (
Finkbeiner & Greenberg, 1996
).
Depolarization and Ca
2
þ
influx also induce the transcription of c-fos by
triggering phosphorylation-dependent activation of transcription factor
cAMP response element binding protein (CREB;
Sheng, McFadden, &
Greenberg, 1990
). Depolarization also recruits the BDNF receptor, TrkB,
to the surface of RGCs (
Meyer-Franke et al., 1998
). Both CREB and TrkB
are known to promote neuronal survival (
Cox, Hengst, Gurskaya,
Lukyanov, & Jaffrey, 2008
; see Volume 106, Chapter 2).
4.2. Depolarization and cAMP elevation
The cAMP concentration is much higher in young neurons. Cultured spinal
neurons with high levels of cAMP survive longer than those with normal
levels (
Hanson, Shen, Wiemelt, McMorris, & Barres, 1998; Michel &
Agid, 1996
). Depolarization increases cAMP in cultured RGCs sufficiently
to enhance their trophic responsiveness (
Shen et al., 1999
). An elevation of
cAMP induces a rapid increase in the surface concentration of full length
TrkB in RGCs and spinal motor neurons in culture (Meyer-Franke
et al., 1998) and increases the expression of
TrkB
gene over a longer period
(
Deogracias, Espliguero, Iglesias, & Rodr´guez-Pe˜a, 2004
).
Addition of forskolin to BDNF, CNTF, and insulin in the culture me-
dium of rat RGCs leads to an effective enhancement of their survival
(Meyer-Franke et al., 1995;
Shen et al., 1999
). Consistent with the
in vitro
experiments, injection of forskolin combined with neurotrophic factors
such as BDNF and/or CNTF significantly increased the
in vivo
survival
