modification of existing substrates. However, he went on to state that, “Process 
II begins within minutes after training and augments for hours or longer; 
Process II is mediated by the synthesis of proteins.” Although the properties of 
Process II fit those of cellular immediate early (CIE) genes, it required another 
decade until this notion could be extended by the specific suggestion that genes 
such as c -fos might mediate this process (Goelet et al. 1986). Several studies 
have been aimed at testing this hypothesis in mammalian models of learning, 
notably long-term potentiation (LTP) (Douglas et al. 1988; Cole et al. 1989; 
Wisden et al. 1990). Although it was thought initially that c -fos expression did 
correlate with the induction of LTP, subsequently conditions could be defined 
whereby LTP could be established in the absence of an induction of c -fos (e.g., 
Cole et al. 1989). However, another CIE gene, egr - 1 (also known as NGFI-A, 
z/7/268, and krox-24), was consistently induced in the hippocampus by the 
stimulus that elicits LTP (Cole et al. 1989; Wisden et al. 1990). Since many CIE 
genes have been identified, it may be no simple matter to determine which, if 
any, are critical in a process such as LTP. Indeed, until strategies become 
available in vertebrates that permit specific interference with CIE gene 
responses, the absolute involvement of particular genes of this class in 
neurophysiological responses must remain an open issue. 
CIE Genes and Kindling 
Although it has drawn the most attention, learning is by no means the only 
example in the nervous system of a process that requires a window of protein 
synthesis concomitant with a stimulus for the establishment of a long-lasting 
effect. For example, kindling is a widely used model of human complex partial 
epilepsy that appears to require protein synthesis for its establishment. The 
kindled state is induced by repeated administration of subconvulsant electrical 
stimuli to various regions of the central nervous system (CNS). Treatment 
with protein synthesis inhibitors during periods of stimulation either blocks or 
attenuates the development of kindling (Cain et al. 1980; Jonec and Wasterlain 
1979). Unlike the genesis of LTP, the induction of CIE genes has a close 
temporal and spatial correlation with the kindling stimulus and the establishment 
of the kindled state (Dragunow and Robertson 1987, 1988; Shin et al. 1990). 
Indeed, both kindling and related seizure paradigms have suggested potential 
target genes and biological consequences for CIE gene induction (reviewed in 
Morgan and Curran 1991a, 1991b). 
Kindling is known to bring about alterations in the levels of several 
neuromodulatory peptides, neurotransmitter receptors, and neurotrophic 
factors. These alterations and their relationship to CIE gene products have 
provided several clues to CIE gene function. First, the overall transcriptional 
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