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

Neural Regeneration Research 2025年第5期20卷 1431-1444页

作者： Yuehua Cui Xiaokuang Ma Jing Wei Chang Chen neha.shakir Hitesch Guirram Zhiyu Dai Trent Anderson Deveroux Ferguson Shenfeng Qiu Basic Medical Sciences University of Arizona College of Medicine-PhoenixPhoenixAZUSA Department of Medicine University of Arizona College of Medicine-PhoenixPhoenixAZUSA

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 *** have previously shown that MET receptor tyrosine kinase in the developing cortical circuits promotes dendritic growth and dendritic spine *** 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 *** 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 *** findings are further corroborated by increased synaptic activity and transient generation of immature silent *** 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 *** data reveal that enhancing MET signaling could be an interventional approach to promote synaptogenesis and preserve functional connectivity in the adult *** findings may have implications for regenerative therapy in aging and neurodegeneration conditions.

关键词： aging circuit connectivity cortical circuits molecular mechanisms neural regeneration neurodegeneration synapses

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

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Neuroscience Bulletin 2023年第6期39卷 881-892页

作者： Chang Chen Jing Wei Xiaokuang Ma Baomei Xia neha.shakir Jessica K.Zhang Le Zhang Yuehua Cui Deveroux Ferguson Shenfeng Qiu Feng Bai Department of Neurology Affiliated Drum Tower HospitalMedical School of Nanjing UniversityNanjing210008China Basic Medical Sciences University of Arizona College of Medicine-PhoenixPhoenixAZ85004USA

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 *** 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 *** mutant APP/PS1 over-expression mouse lines are key tools for studying the molecular mechanisms of AD *** 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 *** 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/Aβ***-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 *** addition,these neurons received smaller amplitude and frequency of miniature excitatory synaptic *** functional disturbances were further corroborated by decreased dendritic spine density and spine head volumes that indicated impaired synapse *** 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 *** 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 *** results suggest that transgenic mutant forms of APP/PS1 overexpression in 5XFAD mice leads to early deve

关键词： Alzheimer’s disease Mouse model Synaptic plasticity Long-term potentiation Cortical circuit Electrophysiology Learning and memory

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