NMDAR (2C) deletion in astrocytes relieved LPS-induced neuroinflammation and depression.

The link between neuroinflammation and depression is a subject of growing interest in neuroscience and psychiatry; meanwhile, the precise mechanisms are still being unrevealed. However, glial cell activation, together with cytokine level elevation, suggests a connection between neuroinflammation and the development or exacerbation of depression. Glial cells (astrocytes) communicate with neurons via their extracellular neurotransmitter receptors, including glutamate receptors NMDARs. However, these receptor roles are controversial and enigmatic in neurological disorders, including depression. Therefore, we hypothesized whether NMDAR subnit NR2C deletion in the astrocytes exhibited anti-depressive effects concurrent with neuroinflammation prevention. To assess, we prepared astrocytic-NR2C knockout mice (G-2C: GFAPCre+Grin2Cflox/flox), followed by LPS administration, behavior tests, and biochemical analysis. Stimulatingly, astrocytic-NR2C knockout mice (G-2C) did not display depressive-like behaviors, neuroinflammation, and synaptic deficits upon LPS treatment. PI3K was impaired upon LPS administration in control mice (Grin2Cflox/flox); however, they were intact in the hippocampus of LPS-treated G-2C mice. Further, PI3K activation (via PTEN inhibition by BPV) restored neuroinflammation and depressive-like behavior, accompanied by altered synaptic protein and spine numbers in G-2C mice in the presence of LPS. In addition, NF-κB and JNK inhibitor (BAY, SP600125) treatments reversed the effects of BPV. Moreover, these results were further validated with an NR2C antagonist DQP-1105. Collectively, these observations support the astrocytic-NR2C contribution to LPS-induced neuroinflammation, depression, and synaptic deficits.

Ceftriaxone averts neuroinflammation and relieves depressive-like behaviors via GLT-1/TrkB signaling.

The beneficial effect of a beta-lactam antibiotic, Ceftriaxone (CEF), to improve depressive-like symptoms has been documented previously, attributed to its modulation of glutamate neurotransmission. Here, we aimed to determine whether CEF could improve LPS-altered glutamatergic signaling associated with neuroinflammation-allied depression. To assess our goals, we established a neuroinflammation-allied depression mice model by injecting lipopolysaccharides (LPS), followed by behavioral and biochemical analysis. LPS-treated mice displayed depressive symptoms, neuroinflammation, dysregulated glutamate and its transporter (GLT-1) expression, altered expression of astrocyte reactive markers (GFAP, cxcl10, steap4, GBP2, and SRGN), and dysregulated BDNF/TrkB signaling. However, these changes were rescued by CEF treatment, as we found decreased neuroinflammation, relief of depression symptoms, and improved GLT-1 and BDNF/TrkB signaling upon CEF treatment. Moreover, GLT-1 and BDNF/TrkB regulation role of CEF was validated by K252a and DHK treatment. In summary, the anti-depressive effects of glutamate modulators, like CEF, are closely related to their anti-inflammatory role.

A novel dopamine D2 receptor-NR2B protein complex might contribute to morphine use disorders.

Dopamine receptors can form heteromeric interactions with other receptors, including glutamate receptors, and present a novel pharmacological target because it contribute to dopamine-dysregulated brain disorders such as addiction and other motor-related diseases. In addition, dopamine receptors D2 (D2Rs) and glutamate NMDA receptors subtype-NR2B have been implicated in morphine use disorders; however, the molecular mechanism underlying the heteromeric complex of these two receptors in morphine use disorders is unclear. Herein, we focus on interactions between D2R and NR2B in morphine-induced conditioned place preference (CPP) and hyperlocomotion mice models. We found that the D2R-NR2B complex significantly increases in morphine-induced mice models, accompanied by ERK signaling impairment, implying the complex could contribute to the morphine addiction pathophysiological process. Further, we design a brain-penetrant interfering peptide (TAT-D2-KT), which could disrupt interactions of D2R-NR2B and decrease addictive-like behaviors concurrent to ERK signaling improvement. In summary, our data provided the first evidence for a D2R-NMDAR complex formation in morphine use disorders and its underlying mechanism of ERK signaling, which could present a novel therapeutic target with direct implications for morphine acquisition and relapse treatment.

eIF4E phosphorylation mediated LPS induced depressive-like behaviors via ameliorated neuroinflammation and dendritic loss.

The translational defect has emerged as a common feature of neurological disorders. Studies have suggested that alterations between opposing and balanced synaptic protein synthesis and turnover processes could lead to synaptic abnormalities, followed by depressive symptoms. Further studies link this phenomenon with eIF4E and TrkB/BDNF signaling. However, the interplay between the eIF4E and TrkB/BDNF signaling in the presence of neuroinflammation is yet to be explored. To illuminate the role of eIF4E activities within LPS-induced neuroinflammation and depression symptomology, we applied animal behavioral, biochemical, and pharmacological approaches. In addition, we sought to determine whether eIF4E dysregulated activities correlate with synaptic protein loss via the TrkB/BDNF pathway. Our results showed that LPS administration induced depressive-like behaviors, accompanied by neuroinflammation, reduced spine numbers, and synaptic protein dysregulation. Concurrently, LPS treatment enhanced eIF4E phosphorylation and TrkB/BDNF signaling defects. However, eFT508 treatment rescued the LPS-elicited neuroinflammation and depressive behaviors, as well as altered eIF4E phosphorylation, synaptic protein expression, and TrkB/BDNF signaling. The causal relation of eIF4E with BDNF signaling was further explored with TrkB antagonist K252a, which could reverse the effects of eFT508, validating the interplay between the eIF4E and TrkB/BDNF signaling in regulating depressive behaviors associated with neuroinflammation via synaptic protein translational regulation. In conclusion, our results support the involvement of eIF4E-associated translational dysregulation in synaptic protein loss via TrkB/BDNF signaling, eventually leading to depressiven-like behaviors upon inflammation-linked stress.

EPO prevents neuroinflammation and relieves depression via JAK/STAT signaling.

AIMS: Erythropoietin (EPO) is a glycoprotein cytokine that exerts therapeutic potential on neurological disorders by promoting neurogenesis and angiogenesis. However, its role as an antidepressant via anti-inflammatory axes is poorly explored. Furthermore, chronic inflammation can induce neuroinflammation, concurrent with depressive-like behaviors that anti-inflammatory and antidepressant agents could avert. Here, we aimed to elucidate the antidepressant potential of Erythropoietin (EPO) in the LPS-induced depression model. MAIN METHODS: For in vivo analysis, mice were treated with LPS (2 mg/kg BW), Erythropoietin (EPO) (5000 U/kg/day), (Ruxolitinib,15 mg/kg), and K252a (25 µg/kg). Depressive-like behaviors were confirmed via behavior tests, including OFT, FST, SPT, and TST. Cytokines were measured via ELISA, while IBA-1/GFAP expression was determined by immunofluorescence. Further, the desired gene expression was measured by immunoblotting. For in vitro analysis, BV2 and N2a cell lines were cultured, treated with LPS, EPO, Ruxolitinib, and K252a, collected, and analyzed. KEY FINDINGS: LPS treatment significantly induced neuroinflammation accompanied by depression-like behaviors in mice. However, EPO treatment rescued LPS-induced changes by averting cytokine production, secretion, and glial cell activation and reducing depressive-like behaviors in mice. Surprisingly, EPO treatment ameliorated LPS-induced JAK2/STAT5 signaling impairment, as validated by JAK2-antagonism. Furthermore, synaptic and dendritic spine defects and BNDF/TrkB signaling upon LPS administration could be prevented by EPO treatment. SIGNIFICANCE: EPO could act as an antidepressant via its anti-inflammatory potential by regulating JAK2/STAT5 signaling.

Adiponectin deficiency accelerates brain aging via mitochondria-associated neuroinflammation.

BACKGROUND: A wide spectrum of changes occurs in the brain with age, from molecular to morphological aspects, and inflammation accompanied by mitochondria dysfunction is one of the significant factors associated with age. Adiponectin (APN), an essential adipokine in glucose and lipid metabolism, is involved in the aging; however, its role in brain aging has not been adequately explored. Here, we aimed to explore the relationship between APN deficiency and brain aging using multiple biochemical and pharmacological methods to probe APN in humans, KO mice, primary microglia, and BV2 cells. RESULTS: We found that declining APN levels in aged human subjects correlated with dysregulated cytokine levels, while APN KO mice exhibited accelerated aging accompanied by learning and memory deficits, anxiety-like behaviors, neuroinflammation, and immunosenescence. APN-deficient mice displayed aggravated mitochondrial dysfunction and HDAC1 upregulation. In BV2 cells, the APN receptor agonist AdipoRon alleviated the mitochondrial deficits and aging markers induced by rotenone or antimycin A. HDAC1 antagonism by Compound 60 (Cpd 60) improved mitochondrial dysfunction and age-related inflammation, as validated in D-galactose-treated APN KO mice. CONCLUSION: These findings indicate that APN is a critical regulator of brain aging by preventing neuroinflammation associated with mitochondrial impairment via HDAC1 signaling.

Roxadustat (FG-4592) abated lipopolysaccharides-induced depressive-like symptoms via PI3K signaling.

Background: Despite its role in inflammation and the redox system under hypoxia, the effects and molecular mechanisms of hypoxia-inducible factor (HIF) in neuroinflammation-associated depression are poorly explored. Furthermore, Prolyl hydroxylase domain-containing proteins (PHDs) regulate HIF-1; however, whether and how PHDs regulate depressive-like behaviors under Lipopolysaccharides (LPS)-induced stress conditions remain covered. Methods: To highlight the roles and underlying mechanisms of PHDs-HIF-1 in depression, we employed behavioral, pharmacological, and biochemical analyses using the LPS-induced depression model. Results: Lipopolysaccharides treatment induced depressive-like behaviors, as we found, increased immobility and decreased sucrose preference in the mice. Concurrently, we examined increased cytokine levels, HIF-1 expression, mRNA levels of PHD1/PHD2, and neuroinflammation upon LPS administration, which Roxadustat reduced. Furthermore, the PI3K inhibitor wortmannin reversed Roxadustat-induced changes. Additionally, Roxadustat treatment attenuated LPS-induced synaptic impairment and improved spine numbers, ameliorated by wortmannin. Conclusion: Lipopolysaccharides-dysregulates HIF-PHDs signaling may contribute to neuroinflammation-coincides depression via PI3K signaling.

Neuronal lack of PDE7a disrupted working memory, spatial learning, and memory but facilitated cued fear memory in mice.

BACKGROUND: PDEs regulate cAMP levels which is critical for PKA activity-dependent activation of CREB-mediated transcription in learning and memory. Inhibitors of PDEs like PDE4 and Pde7 improve learning and memory in rodents. However, the role of PDE7 in cognition or learning and memory has not been reported yet. METHODS: Therefore, we aimed to explore the cognitive effects of a PDE7 subtype, PDE7a, using combined pharmacological and genetic approaches. RESULTS: PDE7a-nko mice showed deficient working memory, impaired novel object recognition, deficient spatial learning & memory, and contextual fear memory, contrary to enhanced cued fear memory, highlighting the potential opposite role of PDE7a in the hippocampal neurons. Further, pharmacological inhibition of PDE7 by AGF2.20 selectively strengthens cued fear memory in C57BL/6 J mice, decreasing its extinction but did not affect cognitive processes assessed in other behavioral tests. The further biochemical analysis detected deficient cAMP in neural cell culture with genetic excision of the PDE7a gene, as well as in the hippocampus of PDE7a-nko mice in vivo. Importantly, we found overexpression of PKA-R and the reduced level of pPKA-C in the hippocampus of PDE7a-nko mice, suggesting a novel mechanism of the cAMP regulation by PDE7a. Consequently, the decreased phosphorylation of CREB, CAMKII, eif2a, ERK, and AMPK, and reduced total level of NR2A have been found in the brain of PDE7a-nko animals. Notably, genetic excision of PDE7a in neurons was not able to change the expression of NR2B, BDNF, synapsin1, synaptophysin, or snap25. CONCLUSION: Altogether, our current findings demonstrated, for the first time, the role of PDE7a in cognitive processes. Future studies will untangle PDE7a-dependent neurobiological and molecular-cellular mechanisms related to cAMP-associated disorders.