The Role of Early Growth Response 1 (EGR1) in Brain Plasticity and Neuropsychiatric Disorders

Abstract

It is now clearly established that complex interactions between genes and environment are involved in multiple aspects of neuropsychiatric disorders, from determining an individual’s vulnerability to onset, to influencing its response to therapeutic intervention. In this perspective, it appears crucial to better understand how the organism reacts to environmental stimuli and provide a coordinated and adapted response. In the central nervous system, neuronal plasticity and neurotransmission are among the major processes integrating such complex interactions between genes and environmental stimuli. In particular, immediate early genes (IEGs) are critical components of these interactions as they provide the molecular framework for a rapid and dynamic response to neuronal activity while opening the possibility for a lasting and sustained adaptation through regulation of the expression of a wide range of genes. As a result, IEGs have been tightly associated with neuronal activity as well as a variety of higher order processes within the central nervous system such as learning, memory and sensitivity to reward. The immediate early gene and transcription factor early growth response 1 (EGR1) has thus been revealed as a major mediator and regulator of synaptic plasticity and neuronal activity in both physiological and pathological conditions. In this review article, we will focus on the role of EGR1 in the central nervous system. First, we will summarize the different factors influencing its activity. Then, we will analyze the amount of data, including genome-wide, that has emerged in the recent years describing the wide variety of genes, pathways and biological functions regulated directly or indirectly by EGR1. We will thus be able to gain better insights into the mechanisms underlying EGR1’s functions in physiological neuronal activity. Finally, we will discuss and illustrate the role of EGR1 in pathological states with a particular interest in cognitive functions and neuropsychiatric disorders.

EGR1 upregulation following Venezuelan equine encephalitis virus infection is regulated by ERK and PERK pathways contributing to cell death

“…Activated ERK is known to phosphorylate serine/threonine residues of more than 50 downstream cytosolic and nuclear substrates (Seger and Krebs, 1995;Pearson et al, 2001). Amoung these substrates, ERK phosphorylates the transcription factor Elk-1 (Cargnello and Roux, 2011), which in turn induces EGR1 gene expression (Tur et al, 2010;Duclot and Kabbaj, 2017b). Previous work has shown the MAPK transduction pathways as key players in the cell death of rat cortical astrocytes (Fernandes et al, 2007), which is in agreement with our results.…”

“…Various extracellular stimuli are capable of activating EGR1 mediating cellular stress responses and being a transcription factor, EGR1 promotes the expression of other genes, as well as its own transcription (Pagel and Deindl, 2011). Furthermore, EGR1 is a major mediator and regulator of synaptic plasticity and neuronal activity in both physiological and pathological conditions (Duclot and Kabbaj, 2017a).…”

Subthalamic nucleus pathology contributes to repetitive behavior expression and is reversed by environmental enrichment

“…In addition, long‐term housing in an enriched environment has been shown to increase the expression of Egr1 previously, although these investigations have been limited to regions of the cortex and hippocampus . In fact, a wide array of environmental manipulations has been shown to affect neuronal activity and intracellular signaling pathways that increase Egr1 expression in the short term, which is followed by Egr1 transcription factor functions that mediate longer lasting neuronal adaptations . These neuronal adaptations include increases in dendritic spine density, an effect we also saw in the STN samples of mice raised in an enriched environment.…”

Genomics studies on musical aptitude, music perception, and practice

“… and ). EGR1 is a functionally interesting gene, as it is a critical mediator of gene–environment interactions characterized by rapid and dynamic responses to neuronal activity and reward‐related synaptic plasticity . IEGs as rapid mediators of signals from the environment serve as plausible candidate genes to detect music .…”