MET receptor tyrosine kinase promotes the generation of functional synapses in adult cortical circuits

Loss of synapse and functional connectivity in brain circuits is associated with aging and neurodegeneration,however,few molecular mechanisms are known to intrinsically promote synaptogenesis or enhance synapse function.We have previously shown that MET receptor tyrosine kinase in the developing cortical circuits promotes dendritic growth and dendritic spine morphogenesis.To investigate whether enhancing MET in adult cortex has synapse regenerating potential,we created a knockin mouse line,in which the human MET gene expression and signaling can be turned on in adult(10–12 months)cortical neurons through doxycycline-containing chow.We found that similar to the developing brain,turning on MET signaling in the adult cortex activates small GTPases and increases spine density in prefrontal projection neurons.These findings are further corroborated by increased synaptic activity and transient generation of immature silent synapses.Prolonged MET signaling resulted in an increasedα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N-methyl-Daspartate(AMPA/NMDA)receptor current ratio,indicative of enhanced synaptic function and connectivity.Our data reveal that enhancing MET signaling could be an interventional approach to promote synaptogenesis and preserve functional connectivity in the adult brain.These findings may have implications for regenerative therapy in aging and neurodegeneration conditions.

Chinese herbal medicine combined with Western medicine for Mycoplasma pneumoniae pneumonia in children:An overview of systematic reviews

Objective:To summarize the characteristics and evaluate the quality of the methodology and evidence within systematic reviews(SRs)of Chinese herbal medicine(CHM)for Mycoplasma pneumoniae pneumonia(MPP)inchildren.Methods:SRs of randomized controlled trials were searched using PubMed,the Cochrane Library,Embase,the Chinese National Knowledge Infrastructure Databases(CNKI),the Chinese Scientific Journals Database(VIP),Wanfang,and the SinoMed Database.SRs on the use of CHM alone or in combination with Western medications for MPP in children were included.The study compared the effects of Western medicine alone with those of CHM.The evidence quality using the A Measurement Tool to Assess Systematic Reviews(AMSTAR)2,the Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA)2020,and the Grading of Recommendations,Assessment,Development,and Evaluation(GRADE)criteria.The primary indicators were the total effective rate,fever subsidence time,and cough disappearance time.The secondary outcomes were pulmonary rale disappearance time,average hospitalization time,lung X-ray infiltrate disappearance time,immunological indices,and inflammatory cytokine levels.Results:Twelve relevant SRs were included;75%(9/12)were assessed as very low quality,and 25%(3/12)Were rated as low quality using the AMSTAR 2 criteria.According to the PRISMA 2020 checklist,the average SR score was 20.3 out of a 27 point maximum.In all SRs,CHM demonstrated improvement in symptoms and signs among children with MPP.The evidence quality using the GRADE criteria ranged from"very low"(>50%)to"moderate"(<5%).The most common downgrading factor was imprecision,followed by publication bias and inconsistency.Conclusion:This overview highlights the limited quality of the methodology and evidence of the included SRs.Although the included studies showed the beneficial effects of CHM on MPP in children,it was difficult to draw firm conclusions owing to methodological flaws.

Disrupted Maturation of Prefrontal Layer 5 Neuronal Circuits in an Alzheimer’s Mouse Model of Amyloid Deposition

Mutations in genes encoding amyloid precursor protein(APP)and presenilins(PSs)cause familial forms of Alzheimer’s disease(AD),a neurodegenerative disorder strongly associated with aging.It is currently unknown whether and how AD risks affect early brain development,and to what extent subtle synaptic pathology may occur prior to overt hallmark AD pathology.Transgenic mutant APP/PS1 over-expression mouse lines are key tools for studying the molecular mechanisms of AD pathogenesis.Among these lines,the 5XFAD mice rapidly develop key features of AD pathology and have proven utility in studying amyloid plaque formation and amyloidβ(Aβ)-induced neurodegeneration.We reasoned that transgenic mutant APP/PS1 over-expression in 5XFAD mice may lead to neurodevelopmental defects in early cortical neurons,and performed detailed synaptic physiological characterization of layer 5(L5)neurons from the prefrontal cortex(PFC)of 5XFAD and wild-type littermate controls.L5 PFC neurons from 5XFAD mice show early APP/Aβimmunolabeling.Whole-cell patch-clamp recording at an early post-weaning age(P22–30)revealed functional impairments;although 5XFAD PFC-L5 neurons exhibited similar membrane properties,they were intrinsically less excitable.In addition,these neurons received smaller amplitude and frequency of miniature excitatory synaptic inputs.These functional disturbances were further corroborated by decreased dendritic spine density and spine head volumes that indicated impaired synapse maturation.Slice biotinylation followed by Western blot analysis of PFC-L5 tissue revealed that 5XFAD mice showed reduced synaptic AMPA receptor subunit GluA1 and decreased synaptic NMDA receptor subunit GluN2A.Consistent with this,patch-clamp recording of the evoked L23>L5 synaptic responses revealed a reduced AMPA/NMDA receptor current ratio,and an increased level of AMPAR-lacking silent synapses.These results suggest that transgenic mutant forms of APP/PS1 overexpression in 5XFAD mice leads to early developmental defects of cortical circuits,which could contribute to the age-dependent synaptic pathology and neurodegeneration later in life.