Genes whose products are induced rapidly and transiently in response to extracellular stimulation

The term immediate early gene (IEG) was borrowed from virology. During the infectious cycle, the viral proteins are expressed in an orderly programme, which involves immediate early, delayed early, and late proteins (Honess and Roizman 1974; Weinheimer and McKnight 1987). For example, in the virus Herpes simplex, products of IEGs are detectable at 1 h of infection, of delayed early genes at 3 h, and of "late response genes at 6-7h (Weinheimer and McKnight 1987). Each "phase in the cascade is required for the initiation of the next phase. An analogous picture was later unveiled in the response of mammalian cells to extracellular stimuli (Nathans et al. 1988; Lanahan et al. 1992). The modified expression of cellular IEGs is detected within minutes of the extracellular stimulation, and commonly lasts only for a short time (e.g. tens of minutes; Sheng and Greenberg 1990).

Some IEGs encode transcription factors (TFs). These are intracellular proteins that control the expression of genes and hence the differentiation, "development, function, and "plasticity of the cell.1 Many TFs are known. A few common encounters in the neurobiological literature are c-Fos, c-Jun, Zif/268, and members of the "CREB/ATF family (Sheng and Greenberg 1990; Hill and Treisman 1995; Herdegen and Leah 1998).2

The genes for certain TFs, such as CREB, are always expressed in the cell to some degree or another. Their products, termed 'constitutive transcription factors' or CTFs, are activated or inhibited by stimulus-triggered post-translational modifications. Other TFs, such as c-Jun, are transiently expressed only upon the proper stimulation. They are termed 'inducible transcription factors', or ITFs. They also undergo post-translational modifications. The post-translational modification of TFs commonly involves phosphorylation by "protein kinases, such as the cyclic adenosine monophosphate-dependent kinases, or the mitogen-activated protein kinase (Hunter and Karin 1992; Xia et al. 1996). TFs are hence components as well as targets of "intracellular signalling pathways. They are capable of coupling short-term events, encoded in the state of the intra-cellular signal transduction pathways, to long-term alterations in the structure and function of the cell. These long-term effects could be mediated by the modulation of the expression of late response genes (Hill and Treisman 1995).

Not all IEGs, however, encode TFs. Many encode membrane and cytoskeletal elements, regulatory proteins, enzymes, and secreted proteins. For example, the extracellular protease (an enzyme that degrades proteins), tissue plasminogen activator, is induced by experience as an IEG in the "hippocampus (Qian et al. 1993). Its role in this case is probably to 'clean' the extracellular space in order to permit tissue remodelling. Another example: a growth factor, brain derived neurotrophic factor, known to be involved in synaptic plasticity in brain, is expressed in the hippocampus as an IEG during "contextual learning (Hall et al. 2000).

Ample data show that the induction of IEGs is correlated with, and sometimes obligatory for, long-term (but not short-term) plasticity and memory (e.g. Impey et al. 1996; Yin and Tully 1996). This is construed within the prevailing conceptual framework ("Zeitgeist), which describes the "consolidation of long-term memory as a growth process that endows the memory with immunity to molecular turnover (Goelet et al. 1986; Dudai 1989; Milner et al. 1998; "development, "protein synthesis). The idea is that, whereas weak training results in only transient post-translational modifications in the neurons, training that involves repetitive or "coincident stimuli induces IEGs, culminating in long-term circuit alterations and therefore long-term memory. The products of the IEGs, or at least of those IEGs that encode TFs, are hence regarded as intracellular switches that transform short-term into long-term plasticity. IEGs have also become a major focus of research in developmental neurobiology (Curran and Morgan 1994; Davis et al. 1996). Indeed, the analysis of the role of gene expression in plasticity is currently an industrious interface between developmental neurobiology on the one hand and the molecular analysis of learning on the other; the two subdisciplines of the neuroscience use the same methodology and terminology (Martin and Kandel 1996; but to put the similarity in proportion, see Con-stantine-Paton and Kline 1998).

The sensitivity to behavioural and physiological manipulations render the induction of IEGs as well as the activation of TFs useful metabolic markers of neuronal activity, which could identify functional circuits in the brain. This is the molecular equivalent of "functional neuroimaging. For example, by monitoring the behaviourally driven expression of the IEG ZENK, Jarvis et al. (2000) have been able to identify a set of forebrain nuclei that subserve the production of "bird-song in the hummingbird. Similarly, c-Fos and other

IEGs have been used to map the circuits of "conditioned taste aversion in the rat (Swank and Bernstein 1994; Lamprecht and Dudai 1995). Given the appropriate IEGs, the "method could also be adapted to supply information on the dynamics of circuit recruitment in a task. This was done using Arc, an IEG that encodes a cytoskeletal-associated protein. The mRNA of Arc is delivered within minutes of its production from the nucleus into the cytoplasm and ultimately into the dendrites. Guzowski et al. (1999) have exploited this property to infer the history of activity of individual neurons in the rat hippocampus at two close time points, as a function of exposure to a novel or familiar environment. As predicted by physiological evidence and by "models of spatial "maps in the hippocampus, Arc was induced in a single subset of hippocampal neurons upon sequential visits of the rat to the same environment, but in two overlapping neuronal subsets upon sequential visits to two different environments.

In spite of the impressive evidence on the involvement of IEGs in learning and memory, the question is yet unsettled whether their role is permissive, or causal, or both. The waves of gene expression that are observed after training could induce alterations in the "internal representations in the circuit, yet could also fulfil "homeostatic functions unrelated to the representational change. Further, IEGs are universal devices; they are induced in all tissues in response to a great variety of stimuli. In neurons, they are also induced in response to stimuli that do not result in a memory. We must therefore identify those contributions of IEGs that are specific to learning and memory, and elucidate their particular contribution in each case. Whether specific, permissive, or obligatory—IEGs are definitely useful ("criterion) in providing cellular explanations for some intriguing behavioural phenomena of learning and memory. For noteworthy examples, see "flashbulb memory and "spaced training.

Selected associations: Consolidation, CREB, Late response genes, Protein synthesis

1For more on transcription factors, see *CREB.

2The names of transcription factors, and hence many IEGs, are usually acronyms that reflect the activity of the molecule, its structure, or the idiosyncratic preferences of the person who first described it. Here is the meaning of names that are mentioned in the text. c-fosstands for '£inkel—Biskis—Jinkins murine osteogenic sarcoma virus', with the 'c' standing for 'cellular', to distinguish it from the viral gene, which is preceded by 'v'.junis 'ju-nana', Japanese for 'number 17', because v-jun was isolated from the avian sarcoma virus 17. zif/268stands for 'zinc finger binding protein clone number 268'; zinc finger denotes a protein DNA-binding domain that centres on a zinc ion. CREB and ATF are explained in *CREB. Arc is 'activity regulated cytoskeletal-associated protein'. Guessing the origin of the name of a transcription factor could be rather frustrating. For example, ZENKis an acronym of the second order, standing for Zif/268, Egr-1, NGFI-A, and Krox-24. Egr is 'early growth response gene', NGFI 'nerve growth factor inducible gene', and Krox is Kruppel-box, where Kruppel is the German-originating name for a mutation that causes bodily deformation in *Drosophila, and 'box' is a generic term for a DNA motif. zif/268, Egr-1, NGFI-A, and Krox-24 all refer to the same of molecular species. Conventionally names of genes are in italics, and of their protein products in regular font. It is not such a bad idea to organize trivia contests on the etymology of the names of transcription factors.

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