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

Chang Chen, Jing Wei, Xiaokuang Ma, Baomei Xia, Neha Shakir, Jessica K. Zhang, Le Zhang, Yuehua Cui, Deveroux Ferguson, Shenfeng Qiu, Feng Bai

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


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 amyloid β (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/Aβ immunolabeling. 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.

Original languageEnglish (US)
Pages (from-to)881-892
Number of pages12
JournalNeuroscience Bulletin
Issue number6
StatePublished - Jun 2023


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

ASJC Scopus subject areas

  • General Neuroscience
  • Physiology


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