Distinctive features of Egr transcription factor regulation and DNA binding activity in CA1 of the hippocampus in synaptic plasticity and consolidation and reconsolidation of fear memory

Abstract

Activity-dependent regulation of Egr1/Zif268, a transcription factor (TF) of the Egr family, is essential for stabilization of dentate gyrus synaptic plasticity and consolidation and reconsolidation of several forms of memory. The gene can be rapidly induced in selective brain circuits after certain types of learning or after recall. Here, we focused on area CA1 and examined regulation of Egr1, Egr2, and Egr3 mRNA and protein, and their DNA binding activity to the Egr response element (ERE) at different times after LTP in vivo and after learning and recall of a fear memory. We found LTP in CA1 leads to rapid induction of the three Egrs, however only Egr1 protein was overexpressed without a co-ordinated change in binding activity, indicating a fundamental difference between CA1 and dentate gyrus LTP. Our investigations in fear memory reveal that both learning and retrieval lead to an increase in binding of constitutively expressed Egr1 and Egr3 to the ERE, but not Egr2. Memory recall was also associated with increased Egr1 protein translation. The nature and temporal dynamics of these changes and tests for interactions between TFs suggest that in addition to ERE-mediated transcription, Egr1 in CA1 may interact with the TF c-Fos to regulate genes via other DNA response elements.

Zif268 / Egr1 gain of function facilitates hippocampal synaptic plasticity and long-term spatial recognition memory

“…Following LTP, there was a small but not significant increase in expression of Zif268 in WT mice (LTP versus control side, Fisher's post hoc p . 0.05; figure 4a) as expected at this relatively late time point [7]. By contrast, in Zif268-overexpressing mice, the increase in Zif268 expression 3 h following LTP reached a high level, significantly above that of the control, non-stimulated sides of the WT and Zif268-overexpressing mice (Zif268-over: LTP versus control side, p , 0.05; Zif268-over LTP side versus WT control side, p , 0.05; figure 4a).…”

“…Consistent with this, Zif268-deficiency was also found to impair the formation of stable hippocampal place cell representations of novel environments [4]. Zif268 mRNA and protein are also rapidly induced in association with LTP and in defined brain structures following learning or recall of several types of memory (see [5,6] for reviews) and this can lead to a functional increase in Zif268 protein binding to its DNA consensus Egr response element (ERE) [7]. Using a gain-of-function strategy in transgenic mice, a recent study reported that enhanced neuronal expression of Zif268 can slow down extinction of conditioned taste aversion [8].…”

The impact of sleep loss on hippocampal function

“…In these studies, selective changes in genes related to presynaptic machinery and synaptic plasticity were identified. Although sleep deprivation modulates gene expression, changes in gene expression are not always indicative of changes in protein expression (Cheval et al 2012;Seibt et al 2012). Vecsey et al (2012) found reduced levels of the mammalian target of rapamycin (mTOR), the protein synthesis regulator, which suggests that protein translation is required for long-term memory formation and plasticity.…”

Global Gene Expression Profile of the Hippocampus in a Rat Model of Vascular Dementia

“…The family of early growth response genes (Egr), containing four members, Egr1, 2, 3, and 4, belong to IEGs that encode transcription factors. Studies reveal that learning and retrieval promote Egr1 translation and lead to an increase in binding of constitutively expressed Egr1 to the Egr response element (ERE) (Cheval et al 2012). Moreover, Egr1 plays a crucial role in memory formation through regulating synaptic transport, synaptic transmission (Koldamova et al 2014), and synaptic plasticity.…”