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

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 

作者机构：Department of NeurologyAffiliated Drum Tower HospitalMedical School of Nanjing UniversityNanjing210008China Basic Medical SciencesUniversity of Arizona College of Medicine-PhoenixPhoenixAZ85004USA 

出 版 物：《Neuroscience Bulletin》 (神经科学通报（英文版）)

年 卷 期：2023年第39卷第6期

页      面：881-892页

核心收录：

学科分类：1002[医学-临床医学] 100203[医学-老年医学] 10[医学] 

基　　金：supported by institutional startup funding from the University of Arizona(to SQ) 

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

摘      要：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 L23L5 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