Rationale: Optic neuritis is one of main symptoms in multiple sclerosis (MS) that causes visual disability. Astrocytes are pivotal regulators of neuroinflammation in MS, and astrocytic yes-associated protein (YAP) plays a critical role in neuroinflammation. Meanwhile, YAP signaling is involved in visual impairment, including glaucoma, retinal choroidal atrophy and retinal detachment. However, the roles and underlying mechanisms of astrocytic YAP in neuroinflammation and demyelination of MS-related optic neuritis (MS-ON) remains unclear. Methods: To assess the functions of YAP in MS-ON, experimental autoimmune encephalomyelitis (EAE, a common model of MS) was established, and mice that conditional knockout (CKO) of YAP in astrocytes, YAP GFAP -CKO mice, were successfully generated. Behavior tests, immunostaining, Nissl staining, Hematoxylin-Eosin (HE) staining, TUNEL staining, Luxol Fast Blue (LFB) staining, electron microscopy (EM), quantitative real-time PCR (qPCR), gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) by RNA sequencing were used to examine the function and mechanism of YAP signaling based on these YAP GFAP -CKO mice and EAE model mice. To further explore the potential treatment of YAP signaling in EAE, EAE mice were treated with various drugs, including SRI-011381 that is an agonist of transforming growth factor-β (TGF-β) pathway, and XMU-MP-1 which inhibits Hippo kinase MST1/2 to activate YAP. Results: We found that YAP was significantly upregulated and activated in the astrocytes of optic nerve in EAE mice. Conditional knockout of YAP in astrocytes caused more severe inflammatory infiltration and demyelination in optic nerve, and damage of retinal ganglion cells (RGCs) in EAE mice. Moreover, YAP deletion in astrocytes promoted the activation of astrocytes and microglia, but inhibited the proliferation of astrocytes of optic nerve in EAE mice. Mechanically, TGF-β signaling pathway was significantly down-regulated after YAP deletion in astrocytes. Additionally, both qPCR and immunofluorescence assays confirmed the reduction of TGF-β signaling pathway in YAP GFAP -CKO EAE mice. Interestingly, SRI-011381 partially rescued the deficits in optic nerve and retina of YAP GFAP -CKO EAE mice. Finally, activation of YAP signaling by XMU-MP-1 relieved the neuroinflammation and demyelination in optic nerve of EAE mice. Conclusions: These results suggest astrocytic YAP may prevent the neuroinflammatory infiltration and demyelination through upregulation of TGF-β signaling and provide targets for the development of therapeutic strategies tailored for MS-ON.

No abstract

Autism spectrum disorder (ASD), a group of neurodevelopmental disorder diseases, is characterized by social deficits, communication difficulties, and repetitive behaviors. Sterile alpha and TIR motif-containing 1 protein (SARM1) is known as an autism-associated protein and is enriched in brain tissue. Moreover, SARM1 knockdown mice exhibit autism-like behaviors. However, its specific mechanism in ASD pathogenesis remains unclear. Here we generated parvalbumin-positive interneurons (PVI)-specific conditional SARM1 knockout (SARM1PV-CKO) mice. SARM1PV-CKO male mice showed autism-like behaviors, such as mild social interaction deficits and repetitive behaviors. Moreover, we found that the expression level of parvalbumin was reduced in SARM1PV-CKO male mice, together with upregulated apoptosis-related proteins and more cleaved-caspase-3-positive PVIs, suggesting that knocking out SARM1 may cause a reduction in the number of PVIs due to apoptosis. Furthermore, the expression of c-fos was shown to increase in SARM1PV-CKO male mice, in combination with upregulation of excitatory postsynaptic proteins such as PSD-95 or neuroligin-1, indicating enhanced excitatory synaptic input in mutant mice. This notion was further supported by the partial rescue of autism-like behavior deficits by the administration of GABA receptor agonists in SARM1PV-CKO male mice. In conclusion, our findings suggest that SARM1 deficiency in PVIs may be involved in the pathogenesis of ASD.

Background Current research on perinatal depression rarely pays attention to the continuity and volatility of depression symptoms over time, which is very important for the early prediction and prognostic evaluation of perinatal depression. This study investigated the trajectories of perinatal depression symptoms and aimed to explore the factors related to these trajectories. Methods The study recruited 550 women during late pregnancy (32 ± 4 weeks of gestation) and followed them up 1 and 6 weeks postpartum. Depressive symptoms were measured using the Edinburgh Postnatal Depression Scale (EPDS). Latent growth mixture modelling (LGMM) was used to identify trajectories of depressive symptoms during pregnancy. Results Two trajectories of perinatal depressive symptoms were identified: “decreasing” (n = 524, 95.3%) and “increasing” (n = 26, 4.7%). History of smoking, alcohol use and gestational hypertension increased the chance of belonging to the increasing trajectories, and a high level of social support was a protective factor for maintaining a decreasing trajectory. Conclusions This study identified two trajectories of perinatal depression and the factors associated with each trajectory. Paying attention to these factors and providing necessary psychological support services during pregnancy would effectively reduce the incidence of perinatal depression and improve patient prognosis.

Neuroinflammation plays a crucial role in the pathogenesis and progression of Alzheimer's disease (AD). The Sterile Alpha and Toll Interleukin Receptor Motif-containing protein 1 (SARM1) has been shown to promote axonal degeneration and is involved in neuroinflammation. However, the role of SARM1 in AD remains unclear. In this study, we found that SARM1 was reduced in hippocampal neurons of AD model mice. Interestingly, conditional knockout (CKO) of SARM1 in the central nervous system (CNS, SARM1 Nestin -CKO mice) delayed the cognitive decline in APP/PS1 AD model mice. Furthermore, SARM1 deletion reduced the Aβ deposition and inflammatory infiltration in the hippocampus and inhibited neurodegeneration in APP/PS1 AD model mice. Further investigation into the underlying mechanisms revealed that the signaling of tumor necrosis factor-α (TNF-α) was downregulated in the hippocampus tissues of APP/PS1;SARM1 Nestin -CKO mice, thereby alleviating the cognitive decline, Aβ deposition and inflammatory infiltration. These findings identify unrecognized functions of SARM1 in promoting AD and reveal the SARM1-TNF-α pathway in AD model mice.

BackgroundOptic neuritis, inflammation of the optic nerve (ON), is one of the main symptoms in multiple sclerosis (MS) and leads to visual disability. Astrocytes are pivotal regulators of neuroinflammation in MS. However, it remains unclear that the detailed roles and mechanisms of astrocytes in the neuroinflammation and demyelination in optic neuritis of MS. MethodsTo assess the role of YAP in ON and retina in response to experimental autoimmune encephalomyelitis (EAE), mice that conditionally knockout (CKO) YAP in astrocytes, namely YAP GFAP -CKO mice, were successfully generated. Immunostaining, Nissl staining, Hematoxylin-Eosin (HE) staining, TUNEL staining, luxol fast blue (LFB) staining, electron microscopy (EM), qRT-PCR and gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) by RNA sequencing were used to examine the roles of YAP pathway in EAE based on these conditional knockout mice. Inhibitors including SRI-011381 [an agonist of transforming growth factor-β (TGF-β) pathway] and XMU-MP-1 (an inhibitor of Hippo kinase MST1/2 to activate YAP) were used to further explore the molecular mechanism of YAP in ON and retina of EAE mice. Additionally, microglia and retinal ganglion cells (RGCs) counts, and demyelination and astrocytes were assessed by immunohistological staining. ResultsWe found that yes-associated protein (YAP) was significantly upregulated and activated in the astrocytes of ON in EAE. Conditional knockout YAP in astrocytes caused more severe inflammatory infiltration and demyelination in ON, and damage of the RGCs in EAE mice. Moreover, YAP deletion in astrocytes promoted the activation of astrocytes and microglia, but inhibited the proliferation of astrocytes of ON in EAE mice. Mechanically, TGF-β signaling pathway was significantly down-regulated after YAP deletion in astrocytes . Additionally, both qPCR and immunofluorescence assays confirmed the reduction of TGF-β 1 in YAP knockout ON astrocytes of EAE mice. Interestingly, SRI-011381 partially rescued the deficits in ON and retina of YAP knockout EAE mice. Finally, activation of YAP pathway relieved the neuroinflammation and demyelination in optic neuritis of EAE mice. ConclusionsThese results suggest astrocytic YAP may prevent the neuroinflammatory infiltration and demyelination through upregulation of TGF-β signaling and provide targets for the development of therapeutic strategies tailored for optic neuritis in MS.