Estrogen Receptor β Regulates Brain Signaling Involved in Depression

Abstract

Depression, a common, costly and recurrent disorder is associated with considerable morbidity and excess mortality. Several epidemiological and clinical studies have reported that women exhibit an increased risk for developing depression in comparison to men. This discrepancy has been attributed to the hormonal fluctuations occurring in the perimenopausal phase, however, the underlying molecular mechanism(s) are currently unknown. In addition, depression and depressive symptoms are common in individuals diagnosed with Late-onset Alzheimer disease (LOAD) and it is now well-established that a significant association exists between depression and LOAD. The human apolipoprotein E (APOE) gene exists as three major isoforms (ε2, ε3, and ε4) and the ε4 allele has been independently associated with a greater incidence for both depression and AD. Although mounting evidence has pointed to the potentially complex interaction between these two brain disorders in which APOE may play a role, the underlying mechanisms are largely unknown. Therefore, the purpose of this thesis was to a) characterize the mechanism(s) that underlie the etiology of depression in perimenopausal females and b) determine the impact of APOE status in the well reported interaction of depression and AD, with depression being an independent risk factor of AD. In the first chapter, we characterized the role of genomic estrogen signaling in the regulation of BDNF and 5HT2A receptor signaling. Our analyses in estrogen receptor (ER) knockout mouse models (ERα-/- and ERβ-/-) demonstrated that BDNF expression was significantly downregulated in ERβ-/- but not ERα-/- mice, and that the ERβ-/--mediated effect was brain-region specific. Further analyses in primary hippocampal neurons indicated that ERβ agonism significantly enhanced BDNF-TrkB signaling and the downstream signaling cascades involved in neurogenesis and synaptic plasticity. Our subsequent analysis in the hippocampus of ERβ-/- rats demonstrated that ERβ deficiency was associated with significantly elevated expression levels of 5HT2A receptor but not 5HT1A receptor. Moreover, our analyses in primary hippocampal neurons revealed that BDNF/TrkB signaling is likely an upstream regulator of the 5HT2A pathway. Collectively, these findings suggest that ERβ signaling dyshomeostasis during perimenopause results in the dysregulation of the BDNF-5HT2A network. These perturbations along with weakened synaptic plasticity may contribute to the overall female susceptibility for depression. Therefore, we hypothesize that timely intervention with an ERβ-targeted modulator could potentially attenuate this susceptibility and reduce the risk or ameliorate the clinical manifestation of depression. In the second chapter, we examined the impact of different APOE isoforms on neurotrophic and serotonergic signaling pathways in female brain. We hypothesized that APOE isoforms differentially regulate BDNF and 5HT2A signaling pathways with APOE4 resulting in overall dysregulation and APOE2 conferring neuroprotection. Our analyses in 6-month-old female humanized APOE mice (ApoE2, ApoE3, and ApoE4) demonstrated that BDNF and 5HT2A receptor expression levels were regulated in a genotype-depended manner with ApoE4 brain exhibiting the lowest level of BDNF and the highest level of 5HT2A. Additionally, several pre- and post-synaptic proteins were significantly downregulated in ApoE4 brain indicating a degree of synaptic deficit. Moreover, we find that chronic administration of an ERβ-targeted phytoestrogenic diet induced a number of changes in ApoE2 and ApoE3 brains, including a significant decrease in the expression of 5HT2A receptor and an increase in BDNF/TrkB and synaptic proteins whereas, in contrast, ApoE4 brain was largely unresponsive to the treatment. Collectively, these results indicate that APOE4 negatively impacts BDNF-5HT2A signaling in female brain, which could, in part, underlie the APOE4-mediated increased risk for depression. The data presented here supports our hypotheses that estrogen signaling significantly regulates BDNF 5HT2A signaling in female brain and thus can provide for a possible mechanistic explanation for depression in perimenopausal females. In addition the data also reveals significant modulation of BDNF 5HT2A signaling pathways and synaptic function in an ApoE genotype dependent manner, thus providing a possible underlying mechanism and therapeutic window for increased risk of AD in depressed patients.