Findings identify GPR151 as a conserved, regionally enriched regulator of behavioral sensitivity to inflammatory challenge and support GPR151 as a candidate therapeutic target for inflammation-associated depression.
Abstract
Background Inflammation-associated depression is a subtype of major depressive disorder that is often resistant to conventional pharmacotherapies, which act in a regionally non-specific manner and therefore also produce unwanted side effects. Here we test GPR151, an orphan GPCR associated with inflammation and highly expressed in the habenula—a region linked to negative valence and depression—as a therapeutic target for inflammation-associated depression. Methods We integrated mouse and human habenular expression analyses with genetic loss-of-function and adult habenular re-expression approaches in mice. Gpr151 knockout mice and littermate controls were exposed to lipopolysaccharide (LPS) inflammatory challenge and assessed for stress coping and motivated behavior, body weight loss, and peripheral immune activation. To test whether adult habenular GPR151 expression is sufficient to restore inflammation-associated behavioral vulnerability, GPR151 was re-expressed in the habenula of knockout mice. Results GPR151 was exceptionally enriched in the habenula and showed conserved topographic organization and similar expression relationships with habenular marker genes in mice and humans. Following LPS challenge, male Gpr151 knockout mice showed reduced passive coping despite body weight loss and immune activation comparable to littermate controls. Adult habenular GPR151 re-expression increased LPS-induced amotivation in male knockout mice without increasing LPS-induced weight loss or immune activation. Female Gpr151 knockout mice also showed reduced passive coping after LPS challenge; however, habenular GPR151 re-expression was insufficient to increase LPS-induced amotivation in females. Conclusions These findings identify GPR151 as a conserved, regionally enriched regulator of behavioral sensitivity to inflammatory challenge and support GPR151 as a candidate therapeutic target for inflammation-associated depression.
GPR55 has attracted attention for its anti-inflammatory, neuroprotective, and neurotransmitter-modulating properties, suggesting a role in mood regulation. Here, we aimed to clarify the contribution of GPR55 to emotional responses.
Male and female GPR55 knockout (GPR55KO) and wild-type (WT) C57BL/6J mice were evaluated in the light-dark box, elevated plus maze, social interaction and tail suspension tests. Gene expression of the GABA
A
receptor α2 and γ2 subunits was measured in the amygdala (AMY). A separate cohort underwent 30 min of restraint stress to assess hypothalamic-pituitary-adrenal (HPA) axis markers, including the expression of the Crf and Nrc3c1 genes in the paraventricular nucleus (PVN) and in the hippocampus.
GPR55 deletion increased anxiety- and depressive-like behaviors across all the behavioral paradigms evaluated. GABA
A
α
2
gene expression in the AMY was elevated in GPR55KO mice of both sexes, while GABA
A
γ
2
expression was not influenced by genotype. Restraint stress increased
Crf
and reduced
Nr3c1
similarly across genotypes. Notably, male GPR55KO mice displayed lower basal
Crf
levels than male controls.
Together, these findings indicate that loss of GPR55 heightens emotional vulnerability and alters specific GABAergic markers in the AMY while preserving HPA axis-related transcriptional response to acute stress. These results support GPR55 as a potential target for the modulation of anxiety- and depression-related states.
Unknown authors· Frontiers in Pharmacology· 0 citations
Introduction Inflammatory processes contribute significantly to the pathophysiology of depression. Although the melanocortin system is well known to regulate inflammation, the specific contribution of melanocortin 1 receptor (MC1R) and its endogenous ligand, α-melanocyte-stimulating hormone (α-MSH), to inflammation-associated depression remains unclear. Methods Systemic lipopolysaccharide (LPS) administration was used to establish an inflammation-associated depression model in mice. Depressive-like behaviors, synaptic functions, and metabolic alterations were evaluated using behavioral tests, patch-clamp recordings, and untargeted metabolomic profiling. To examine the functional involvement of MC1R, adeno-associated virus (AAV)-mediated selective Mc1r overexpression was performed in the medial prefrontal cortex (mPFC). Results LPS administration induced depressive-like behaviors in mice, accompanied by microglial activation and a significant reduction in MC1R expression in the prefrontal cortex (PFC). Treatment with MC1R endogenous ligand α-MSH mimetic Nle4-DPhe7-α-MSH (NDP-MSH) markedly attenuated LPS-induced depressive-like behaviors, enhanced MC1R, postsynaptic density protein 95 (PSD95), glutamate receptor 1 (GluA1) and protein kinase A (PKA) phosphorylation. PKA inhibitor H89-mediated inhibition of the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway partially but robustly abolishes the behavioral, anti-inflammatory, and synaptic protective effects of NDP-MSH. Additionally, untargeted metabolomics confirmed that NDP-MSH effectively corrected LPS-induced metabolic dysregulation, a therapeutic effect that was robustly suppressed by H89; this metabolic remodeling was closely associated with purine metabolism, pantothenate, and coenzyme A biosynthesis. Critically, AAV-mediated Mc1r overexpression in the mPFC was sufficient to rescue LPS-induced depressive-like phenotypes. Conclusion This study highlights MC1R-related signaling in the PFC as an important contributor to inflammation-associated depression and suggests that NDP-MSH alleviates inflammation-associated depressive-like behaviors in association with melanocortin signaling involving MC1R and downstream cAMP/PKA activation.
Shanglan Qu, Xin Peng, Jieyu Ji et al.· Frontiers in Pharmacology· 0 citations
Results suggest that Adgrd1 plays a key role in maintaining hippocampal resilience and regulating motivational behaviors through integrated molecular and circuit-level mechanisms.
Inés Martínez-Soria, Pol Picón-Pagès, A. P. Pérez González et al.· bioRxiv· 0 citations
BACKGROUND AND PURPOSE
Microglia are central regulators of neuroinflammation in depression. Drivers involved remain incompletely understood. Sigma non-opioid intracellular receptor 1 (S1R) is involved in brain inflammation. This study investigates how S1R regulates neuroinflammation associated with depression.
EXPERIMENTAL APPROACH
Using integrated machine learning and single-cell transcriptomics, a key gene implicated in microglial dysfunction in depression was identified. Its relevance was examined in a lipopolysaccharide (LPS)-induced mouse model of depression and LPS-stimulated BV-2 cells. Further, targeted knockdown or overexpression of this gene was performed on medial prefrontal cortex (mPFC) microglia, followed by integrated behavioural, cellular and molecular analyses.
KEY RESULTS
Plxdc2 was the key gene up-regulated at both transcriptional and protein levels in blood and depression-susceptible brain regions. Single-cell RNA sequencing confirmed its specific enrichment in microglia, particularly within inflammatory gene sets related to N-linked glycosylation (NLG). LPS-treated mice, depressive-like behaviours were accompanied by elevated expression of Plxdc2 and the glycosylation-related enzyme β-1,4-galactosyltransferase 1 in mPFC microglia. The S1R agonist Hypidone hydrochloride (YL-0919) or conditional knockdown of Plxdc2, reversed these molecular changes, reduced neuroinflammation and alleviated depressive-like behaviours. Analysis demonstrated that overexpressing Plxdc2 in mPFC microglia activated the JAK2-STAT1 pathway, enhanced NLG, shifting microglia towards a pro-inflammatory phenotype, worsening deficits in synaptic plasticity and induced depressive-like behaviour. These were reversible by the NLG inhibitor tunicamycin.
CONCLUSIONS AND IMPLICATIONS
Plxdc2 promotes depressive-like behaviours by dysregulating NLG-mediated inflammatory in microglia. S1R activation has a therapeutic effect by inhibiting this pathway, positioning the S1R-Plxdc2 axis as a potential target for modulating microglial function in inflammation-related depression.
Jing-ya Wang, Peng Ren, De-yi Yang et al.· British Journal of Pharmacol...· 0 citations
G Protein-Coupled Receptors (GPCRs) are the most widely used drug targets in neuropsychiatric disorders. GPR158, an orphan class C GPCR, is highly enriched in the central nervous system and has emerged as a critical regulator of stress-related depression. However, its precise mechanisms in depression remain incompletely understood. This review aims to establish a systematic framework spanning the molecular structure to physiological function, highlighting the role of GPR158 in the onset and progression of depression. We summarize the expression pattern, unique structural features, novel ligands, and downstream signaling pathways of GPR158, with a focused discussion on its multiple regulatory mechanisms in depression, including Cyclic Adeno-sine Monophosphate (cAMP) signaling, neuronal excitability, Brain-derived Neurotrophic Factor (BDNF) translation, glutamatergic transmission, and mitophagy. Abnormally upregulated GPR158 in the prefrontal cortex and hippocampus promotes depressive-like behaviours, whereas knockout or inhibition of GPR158 exerts antidepressant-like effects. These findings not only reveal the potential regulatory function of GPR158 in the pathological process of depression but also provide a solid theoretical basis for the development of antidepressant drugs targeting GPCRs, facilitating the subsequent development of more accurate and efficient antidepressant candidate drugs.
Unknown authors· Current Neuropharmacology· 0 citations
These findings suggest that MRs in GABAergic neurons normally function as critical constraints on excitatory synaptic plasticity during high-stress states, underscoring that adaptive stress responses rely on a finely tuned, cell-type-specific balance of corticosteroid signaling within limbic microcircuits.
Huanqing Yang, V. Kovářová, Alena O. Godunova et al.· Neurobiology of Stress· 0 citations
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