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and axonal regeneration of axotomized RGCs in the rat and cat retinas (
Cui,
Yip, Zhao, So, & Harvey, 2003; Park, Luo, Hisheh, Harvey, & Cui, 2004;
Watanabe, Tokita, Kato, & Fukuda, 2003
). The effects of cAMP elevation
are mimicked by depolarization induced either by high K
þ
or by glutamate
receptor activation, both of which elevate the cAMP levels in the RGCs by
activating a calcium-dependent type-1 adenylyl cyclase (Meyer-Franke
et al., 1995). Depolarization and cAMP elevation also enhanced responsive-
ness of the adrenal medullary-derived neuronal cell line to nerve growth fac-
tor (NGF) by upregulating transcription of NGF receptor TrkA (
Birren,
Verdi, & Anderson, 1992
). Thus, cAMP is a critical player in the electrical
activity-induced survival of neurons.
4.3. Electrical stimulation
Direct electrical stimulation can alter the survival rates of isolatedCNS neurons in
a dose-dependent manner (
Kaplan et al., 1988
). Electric fields (EFs) enhance the
regeneration of damaged neurons of the PNS and CNS in animals as diverse as
lampreys,frogs,rats,andguineapigs(
McCaig &Rajnicek, 1991
). Neurons have
either a cathodal preference (
Jaffe & Poo, 1979
) or an anodal preference (
Cork,
McGinnis, Tsai, & Robinson, 1994
) when exposed to an EF. Rat hippocampal
neurons oriented their axons perpendicularly to the direction of the applied elec-
trical field of physiological magnitude, apparently at the expense of cathodally di-
rected neurites (
Rajnicek,Gow,&McCaig,1992
). Electrical activity influences
the axonal path finding of developing neurons. Brief periods of electrical stimu-
lation of cultured Xenopus spinal neurons resulted in a marked alteration in the
turning responses of the growth cone induced by gradients of attractive or repul-
sive guidance cues. This effect required the presence of extracellular Ca
2
þ
during
electrical stimulation and appeared to be mediated by an elevation of both cyto-
plasmic Ca
2
þ
and cAMP (
Ming, Henley, Tessier-Lavigne, Song, & Poo, 2001
).
Stimulation of the RGCs by electrical pulses from a silicon chip enhanced their
survival and axonal growth in response to BDNF
in vitro
(
Goldberg et al., 2002
).
Thus, electrical stimulation modulates multiple neuronal processes.
5. SURVIVAL-PROMOTING EFFECTS OF ELECTRICAL
ACTIVITY ON NEURONS IN VIVO
In
in vivo
studies of the neuroprotective effects of neuronal activity,
different methods have been used to increase the electrical activity of neu-
rons, for example, direct electrical stimulation of the nervous system, or nor-
mal physiological stimulation such as exercise and light exposure, that
stimulate the entire nervous system.
