Abstract
Hypothalamic dysfunction is a key pathological factor in inflammation-associated depression. In the present study, isobaric tags for relative-absolute quantitation (iTRAQ) combined with mass spectrometry and gas chromatography-mass spectrometry (GC-MS) were employed to detect the proteomes and metabolomes in the hypothalamus of the lipopolysaccharide (LPS)-induced depression mouse, respectively. A total of 187 proteins and 27 metabolites were differentially expressed compared with the control group. Following the integration of bi-omics data, pertinent pathways and molecular interaction networks were further identified. The results indicated altered molecules were clustered into Ephrin receptor signaling, glutamatergic transmission, and inflammation-related signaling included the LXR/RXR activation, FXR/RXR activation, and acute phase response signaling. First discovered in the hypothalamus, Ephrin receptor signaling regulates N-methyl-D-aspartate receptor (NMDAR)-predominant glutamatergic transmission, and further acted on AKT signaling that contributed to changes in hypothalamic neuroplasticity. Ephrin type-B receptor 2 (EPHB2), a transmembrane receptor protein in Ephrin receptor signaling, was significantly elevated and interacted with the accumulated NMDAR subunit GluN2A in the hypothalamus. Additionally, molecules involved in synaptic plasticity regulation, such as hypothalamic postsynaptic density protein-95 (PSD-95), p-AKT and brain-derived neurotrophic factor (BDNF), were significantly altered in the LPS-induced depressed group. It might be an underlying pathogenesis that the EPHB2-GluN2A-AKT cascade regulates synaptic plasticity in depression. EPHB2 can be a potential therapeutic target in the correction of glutamatergic transmission dysfunction. In summary, our findings point to the previously undiscovered molecular underpinnings of the pathophysiology in the hypothalamus of inflammation-associated depression and offer potential targets to develop antidepressants.
Highlights
Depression, characterized by depressed mood, diminished interests, avolition, worthlessness and hopelessness, raises concern in global public health (Otte et al, 2016)
CD-1 mice were challenged with LPS (0.83mg/kg, i.p.; named LPS mice in following) or saline followed by weighing at 24 h i.p. and submitted to assessment of depressive-like behavior before euthanization for hypothalamus collection
Our results were attributed to the following significant findings: (1) liver X receptor (LXR)/retinoid X receptor (RXR) activation, farnesoid X receptor (FXR)/RXR activation, and acute phase response signaling were primarily clustered into immunity and inflammationrelated signaling, which indicated initiating factor of LPSinduced depression mouse model: “neuroinflammation.” (2) Perturbation of glutamatergic transmission and Ephrin receptor signaling were significant among the changed pathways; (3) The impairments of hypothalamic neuroplasticity were regulated by Ephrin receptor signaling, which influenced the GluN2A mediated glutamatergic transmission and protein kinase B (AKT) signaling; (4) Ephrin type-B receptor 2 (EPHB2) and GluN2A may be potential therapeutic targets for depression
Summary
Depression, characterized by depressed mood, diminished interests, avolition, worthlessness and hopelessness, raises concern in global public health (Otte et al, 2016). The lifetime prevalence of depression is estimated at 2–20%, and more than 60% of depression cases jeopardize the quality of life (Zilcha-Mano et al, 2014; Ribeiro et al, 2018). Among the currently known pathogenetic factors, inflammation has been considered an important pathologic factor of depressive disorders in vulnerable individuals, such as patients with systemic infections, diabetes, cancers, or autoimmune diseases, etc. Increasing evidence has highlighted several mental illnesses including depression have been linked to HPA axis dysfunctions (Jacobson, 2014; Rao et al, 2016). Regulating the function of the HPA axis in inflammation-associated depression remains poorly understood
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