EGR3 Immediate Early Gene and the Brain-Derived Neurotrophic Factor in Bipolar Disorder

Abstract

Bipolar disorder (BD) is a severe psychiatric illness with a consistent genetic influence, involving complex interactions between numerous genes and environmental factors. Immediate early genes (IEGs) are activated in the brain in response to environmental stimuli, such as stress. The potential to translate environmental stimuli into long-term changes in brain has led to increased interest in a potential role for these genes influencing risk for psychiatric disorders. Our recent finding using network-based approach has shown that the regulatory unit of early growth response gene 3 (EGR3) of IEGs family was robustly repressed in postmortem prefrontal cortex of BD patients. As a central transcription factor, EGR3 regulates an array of target genes that mediate critical neurobiological processes such as synaptic plasticity, memory and cognition. Considering that EGR3 expression is induced by brain-derived neurotrophic factor (BDNF) that has been consistently related to BD pathophysiology, we suggest a link between BDNF and EGR3 and their potential role in BD. A growing body of data from our group and others has shown that peripheral BDNF levels are reduced during mood episodes and also with illness progression. In this same vein, BDNF has been proposed as an important growth factor in the impaired cellular resilience related to BD. Taken together with the fact that EGR3 regulates the expression of the neurotrophin receptor p75NTR and may also indirectly induce BDNF expression, here we propose a feed-forward gene regulatory network involving EGR3 and BDNF and its potential role in BD.

Keywords: bipolar disorder; brain-derived neurotrophic factor (BDNF); early growth response gene 3 (EGR3); immediate early genes; neuroplasticity; regulatory network.

Figure 1

Representation of early growth response gene 3 (EGR3) signaling cascade in neurons, focused on brain-derived neurotrophic factor (BDNF) signaling leading to EGR3 expression. EGR3 is activated downstream of numerous proteins, including BDNF through binding to its receptor TrkB. In turn, EGR3 protein activates numerous downstream target genes. Examples include: type A GABA receptor (GABRA), NGFR (p75NTR) receptor, the activity regulated cytoskeletal associated gene (Arc) and triggering receptor expressed on myeloid cells 1 (TREM-1), as well as, though perhaps indirectly, NMDA receptor (NMDAR). These genes are each involved in critical neurobiological processes such as neuroplasticity, memory and learning and adaptation to stress. It is important to note that EGR3 may indirectly induce BDNF expression via regulation of NMDAR, the activation of which stimulates BDNF synthesis. Thus, we propose a feed-forward regulatory gene network involving EGR3 and BDNF that regulates neuronal gene expression in response to endogenous or environmental stimuli which, when disrupted, may lead to bipolar disorder (BD) pathophysiology.

Figure 2

Proposed link between BDNF and EGR3 and their potential role in BD. Lower BDNF levels observed in BD patients may influence the reduced EGR3 levels seen in BD since BDNF regulates EGR3. EGR3 may also indirectly induce BDNF expression via regulation of NMDAR. Thus, we also suggest that reduced EGR3 expression, as we have seen in BD patients in our study, could contribute to lower BDNF levels associated with this illness. Based on these findings, we propose a feedback-loop reinforcing this dysfunctional pathway that could, in turn, impair neuroplasticity and resilience. This process may ultimately lead to increased vulnerability to stress, and could result in alterations in several biological factors that contribute to BD, such as abnormal structural brain changes and the associated cognitive and functional decline (a process called neuroprogression). The neural circuits additionally disrupted in this process could contribute to an impaired neuroplasticity and resilience, increasing vulnerability to stress and mood episodes and reduced responsiveness to pharmacotherapy, thus perpetuating a vicious cycle in illness progression.