decreases in FLI when glutamate was used as the stimulus. However, it is 
possible that the observed effect might be unique to cultured, fetal cortical 
neurons and not be a general phenomenon of developing or mature cortical 
neurons in vivo. However, preliminary data in the authors’ laboratory suggest 
that NMDA antagonists can block translation, but not transcription, of the c -fos 
gene in the intact mammalian brain. 
Nevertheless, the mechanism by which NMDA receptors might inhibit induction 
of Fos protein, but not c -fos mRNA, by VIP, FGF, zinc, and other stimuli is 
potentially very interesting. There are at least three possible mechanisms. 
First, it is conceivable that activation of the NMDA receptor is necessary for 
posttranslational processing of Fos or for phosphorylation of Fos. If the authors’ 
polyclonal antibody does not recognize unprocessed or unphosphorylated 
Fos protein, then the data would show that the NMDA receptor is essential 
for the posttranslational processing or phosphorylation that would make it 
possible to immunostain the protein in culture. This seems unlikely since other 
polyclonal antibodies to Fos detect unphosphorylated and phosphorylated 
Fos (Sonnenberg et al. 1989). Second, it is possible that the NMDA receptor 
might downregulate protease activity in some undescribed fashion. For 
example, NMDA receptor blockade could lead to overactivity of a protease 
that leads to rapid degradation of the Fos protein so that it was not detectable 
immunocytochemically. There is little precedent for this. Third, and most likely, 
is the possibility that the NMDA receptor is somehow involved in translation of 
c -fos mRNA to Fos protein. This could occur via calcium entry through the 
NMDA channel. Regulation of translation does occur in other systems. 
Expression of yeast transcription activator GCN4 (whose DNA binding site 
is related to the Fos-Jun binding site) is regulated at the translational level. 
External stimuli appear to activate a protein kinase that mediates translational 
regulation of GCN4 mRNA (Hinnebusch 1990). In addition, one calcium- 
calmodulin kinase affects translation by phosphorylating the elongation factor 
2 (Ryazanov et al. 1988). 
If NMDA antagonists are shown to block induction of Fos protein, but not c -fos 
mRNA, from a variety of stimuli, these results could have important implications. 
NMDA antagonists cause learning impairment (Morris et al. 1986) and prevent 
plasticity in cortex and other brain regions (McDonald and Johnston 1990). Fos 
could play a role in NMDA-mediated plasticity by producing long-term changes 
in gene expression related to a variety of extracellular signals. The authors’ 
results suggest that if neurotrophic factors and neurotransmitters mediate 
plasticity by induction of c -fos mRNA, the expression of Fos protein by these 
agents requires concurrent activation of the NMDA receptor. Therefore, 
blockade of NMDA receptors not only prevents direct NMDA-mediated events 
but also prevents induction of Fos protein from a variety of other extracellular 
signals. 
177 
