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.