ReviewHow necessary is the activation of the immediate early gene zif268 in synaptic plasticity and learning?
Introduction
The immediate early genes (IEGs) are a class of genes that are rapidly and transiently activated in response to neuronal activation; they require no protein synthesis to be activated and, upon activation, can in turn activate downstream targets. To date they are generally described as either ‘regulatory IEGs’ which encode proteins that may increase or decrease ‘downstream’ gene expression or ‘effector IEGs’ encoding proteins which have a more direct functional role at the synapse. Lanahan and Worley [1] have estimated that approximately 30–40 genes are neuronal IEGs and of these about 10–15 are regulatory genes such as c-fos and zif268, while the rest are effector genes, such as arg3.1, Homer and BDNF. The protein products of the regulatory genes are classified as inducible transcription factors, as opposed to the constitutively expressed transcription factors, such as CREB and Elk-1, that are regulated by post-translational modification, such as phosphorylation.
The potential functional role of the IEGs began to be realised in the late 60s and early 70s, developing out of early cancer research. Although originally described as viral oncogenes, which were required for viral replication and the development of tumours, it was later shown that these genes were present in the DNA of all vertebrates and that they responded to growth factors or mitogens. Because regulatory IEGs control the synthesis of proteins that can bind to DNA, thereby regulating the activation of downstream target genes, it lead to the notion that the normal function of these IEGs was to trigger the genomic response to mitogen-stimulated activation of the cell (see [2] for review).
Following the report that the protooncogene and transcription factor c-fos was rapidly and transiently induced in the brain following seizure activity or kindling [3], [4], [5] studies in both c-fos and other immediate early genes have characterised the activation of these genes by stimulation of cell surface receptors, induced via various different stimuli (see [1], [2], [6] for reviews). As these studies have shown IEGs to be rapidly and transiently activated, and their activation is resistant to inhibitors of protein synthesis, it further suggested that this class of genes may constitute an early genomic response required for triggering the mechanisms underlying persistent cell modification. An important biological function of these modifications in neurons may be to underlie the maintenance or stabilisation of neuronal plasticity and the formation of long-term memories.
To date, long-term potentiation (LTP) has been considered to be the most viable experimental model of the type of synaptic modifications necessary for the encoding and storage of memories that would occur in neuronal networks (see reviews by Miller and Mayford [7]; Elgersma and Silva [8]; Martin et al. [9]; Thompson [10]). It has been established that there is at least an early and a late phase of LTP that is subserved by different cellular and molecular mechanisms. The early phases of LTP are under the control of second messengers and kinases [11] whereas the late phases of LTP, on the order of 3–6 h after induction, are dependent on transcriptional and translational activity in cells [12], [13], [14], [15], [16], a phase of plasticity that may be initiated by the IEGs. In a parallel manner, inhibiting the synthesis of new proteins following learning blocks the consolidation of memories [17], [18]. As the IEGs lie within a cascade of signalling events where they are activated by kinases, and in turn, interact either with downstream genes or proteins at the synapses to induce enduring modifications of the cell, it is strongly believed that activation of the IEGs may constitute a critical triggering mechanism that may subserve the maintenance of synaptic plasticity and the long-term storage of memories. Therefore, understanding how the regulation of IEGs occur in both synaptic plasticity and learning as well as knowing the upstream activators and the downstream targets of the IEGs may shed light on some of the mechanisms implicated in the processing of the memory trace. Of the known IEGs, those that have been most studied in terms of the control of synaptic plasticity and the formation of long-term memories are c-fos, zif268 and arg3.1. In this review, we primarily focus on the potential role of zif268 in these mechanisms.
Section snippets
Characteristics and properties of zif268 and other members of the Egr family
The zif268 (also known as Krox 24, NGFI-A, Egr-1, TZS8 and Zenk) was discovered as an immediate early gene by its response to nerve growth factor treatment resulting in neuronal differentiation, and by its response to serum treatment resulting in mitosis [19], [20], [21], [22]. The gene encodes an 82 and an 88 kDa protein, depending on the initiation sequence [23] and its predominant distinguishing feature, and that of the other members of the Egr family, is the 3 zinc finger sequences in the
Regulation and requirement of zif268 mRNA during synaptic plasticity
The first two studies to investigate whether zif268 was regulated by synaptic plasticity were conducted in the dentate gyrus of the hippocampus [43], [44]. These authors found that tetanic stimulation of the perforant path to induce LTP at dentate gyrus synapses resulted in ipsilateral upregulation of the gene between 30 and 60 min post-tetanus. Upregulation of the gene required similar threshold intensity that is necessary to induce LTP. Regulation of the gene was susceptible to blockade of the
Regulation and requirement of zif268 during learning
In comparison with the number of reports that have shown activation of the immediate early gene c-fos in various forms of learning (see [77], [78] for reviews) there are much fewer studies on the regulated transcription of zif268. In general, it appears that zif268 is rapidly regulated during associative learning, such as song learning in birds [79], [80], [81], [82], visual paired associations in the monkey [83], fear associated learning tasks in rats [84], [85], [86], [87], and spatial
How important is the activation of zif268 for the processing of memories?
To date some 30–40 immediate early genes have been identified, and these genes primarily act, as described by Herdegen and Leah [34], as ‘master regulators of every cell’s development and function’. Given these genes are highly reactive to wide ranging stimuli, it beggars the question as to what exactly is the role of these genes in adult synaptic plasticity and learning. There is fairly widespread agreement that the IEGs are the ‘gateway to the genomic response’, where downstream target genes
Acknowledgements
We would like to thank P. French for the in situ hybridisation and immunocytochemical images. The work described by Jones et al. [50] and Bozon et al. [112] in this manuscript was supported by CNRS PICS programme (No 756).
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