Early Disruption of Synaptic Function, Impairment of Plasticity, and Decreased of Cortical Circuit Connectivity in an Alzheimer’S Mouse Model of Amyloid Deposition

Abstract

Mutations in genes encoding amyloid precursor proteins and presenilins lead to increased β-amyloid (Aβ) production and cause familial Alzheimer’s disease (AD), a neurodegenerative disorder often associates with aging and features synapse loss and impaired synaptic plasticity. Aβ deposition is a pathological hallmark of AD. It is currently unknown whether and how AD risk alleles affects development of brain circuit function, and whether subtle synaptic pathology occurs prior to overt Aβ deposition. Transgenic mutated APP/PS1 over-expression mice lines are key tools to study molecular mechanisms of AD pathogenesis. Among these mice lines, the 5XFAD mice rapidly recapitulate key features of AD pathology, and have proven utility in studying amyloid plaque formation and Aβ-induced neurodegeneration. We reason that transgenic mutant APP/PS1 over-expression may lead to neurodevelopmental defects in early cortical neurons as a result of continuous APP/Aβ expression from early life. We first explored age-dependent plasticity changes in prefrontal cortical circuits in the 5XFAD mice, and found that at an early age (6-8 wks old) that does not produce overt impairment of hippocampus LTP, layer (L) 5 neuron circuit plasticity, measured by long term potentiation (LTP), is impaired. In addition, L5 neurons, which are reportedly vulnerable cortical neuron populations, show reduced mEPSC amplitude and frequency in early postweaning ages, indicating impaired synaptic transmission as a result of transgenic APP/Aβ overloading during early postnatal development. These functional changes were corroborated by the morphological findings of smaller, sparser dendritic spines on L5 pyramidal neurons, indicative of impaired prefrontal circuit function. Lastly, laser scanning photostimulation (LSPS) combined with glutamate uncaging revealed that L2/3 > L5 cortical connectivity was decreased at this early age. Our results suggest 5XFAD transgenic mutant APP/PS1 over expression causes developmental defects of cortical circuits, which could contribute to the age-dependent synaptic pathology and neurodegeneration later in life.