First, it is not clear that c -fos can be induced in all neural cells. For example, 
tactile whisker sensory stimulation does not induce c-fos in any whisker-related 
pathway. However, section of the infraorbital nerve to the whiskers induces c- 
fos in the spinal trigeminal nucleus pars caudalis and decreases c -fos 
expression in whisker barrel cortex contralateral to the lesion (Sharp et al. 
1989b). Therefore, depolarization of neurons in vivo may be necessary, but 
it is not a sufficient stimulus to induce c -fos. This is supported by the finding 
that light stimulation, which should activate most retinal neurons, induces Fos 
in a small subpopulation of retinal neurons (Sagar and Sharp 1990). Since 
depolarization alone cannot account for induction of c -fos, either specific 
transmitters or the concurrent actions of several extracellular signals might be 
required for the induction of c -fos in neurons. The concurrent activation of two 
extracellular receptors has been shown to be important for induction of the c-fos 
gene (Curran and Morgan 1985). 
Mechanisms of c -fos induction in glia appear to be different. In most in vivo 
studies, c -fos appears to be induced in neurons and not in glia. However, 
Dragunow and Robertson (1988) showed that FLI was induced in glial-like cells 
at the sites of cortical injury. This was confirmed by Sharp and colleagues 
(1990). To better define the stimuli responsible for c -fos induction in glia 
following injury, several groups have studied c -fos in cultured glia. Arenander 
and coworkers (1989) found that mitogens and stellation agents induced 
immediate early genes in cultured rat astrocytes. Hisanaga and coworkers 
(1990a) showed that c -fos is induced in astrocytes with agents that promote 
differentiation or proliferation, but c-/bs is not induced in astrocytes with 
depolarizing agents. Sagar and colleagues (1991) have shown that epidermal 
growth factor (EGF) and transforming growth factor alpha induce c-/bs mRNA 
and Fos protein in identified Muller glial cells of the rabbit retina in vivo. 
Therefore, it is possible that induction of c -fos in glial cells at sites of injury 
is related to local release of trophic factors that act directly on glia. 
Induction of c -fos in cortical neurons has been linked to activation of glutamate 
receptors. Sonnenberg and colleagues (1989) showed that various glutamate 
agonists, including N-methyl-D-aspartate (NMDA) and kainate, induce Fos, Fos- 
related antigen, and activator protein-1 DNA-binding activity in the mouse brain. 
Dragunow and Robertson (1988) and Sharp and coworkers (1989b) showed 
that cortical injury induced c-fos in neurons throughout ipsilateral cortex. Sharp 
and coworkers (1989b) showed that injection of quinolinic acid, an NMDA 
agonist, into cortex markedly induced Fos throughout the ipsilateral hemisphere 
compared with saline-injected subjects. Prior injection of the noncompetitive, 
NMDA receptor blocker, MK801 , into the ventricle before local injury or 
quinolinic acid injections prevented Fos induction in the ipsilateral hemisphere. 
These data suggested that the NMDA receptor mediated cortical induction of c- 
fos in neurons following cortical injury. 
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