Novel Quantitative Analyses of Spontaneous Synaptic Events in Cortical Pyramidal Cells Reveal Subtle Parvalbumin-Expressing Interneuron Dysfunction in a Knock-In Mouse Model of Alzheimer’s Disease

Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder that has become a compelling global public health concern. Besides pathological hallmarks such as extracellular amyloid plaques, intracellular neurofibrillary tangles, and loss of neurons and synapses, clinical reports have shown that epileptiform activity, even seizures, can occur early in the disease. Aberrant synaptic and network activities as well as epileptiform discharges have also been observed in various mouse models of AD. The new App NL-F mouse model is generated by a gene knock-in approach and there are limited studies on basic synaptic properties in App NL-F mice. Therefore, we applied quantitative methods to analyze spontaneous excitatory and inhibitory synaptic events in parietal cortex layer 2/3 pyramidal cells. First, by an objective amplitude distribution analysis, we found decreased amplitudes of spontaneous inhibitory postsynaptic currents (sIPSCs) in aged App NL-F mice caused by a reduction in the amplitudes of the large sIPSCs with fast rates of rise, consistent with deficits in the function of parvalbumin-expressing interneurons (PV INs). Second, we calculated the burstiness and memory in a series of successive synaptic events. Lastly, by using a novel approach to determine the excitation to inhibition (E/I) ratio, we found no changes in the App NL-F mice, indicating that homeostatic mechanisms may have maintained the overall balance of excitation and inhibition in spite of a mildly impaired PV IN function. Significance Statement Using novel quantitative analyses of spontaneous synaptic currents in L2/3 pyramidal cells, we revealed subtle deficits in the function of parvalbumin-expressing interneurons (PV INs) in a new mouse model of AD, the App NL-F mice. We applied novel statistical and analytical methods to further characterize the properties of spontaneous postsynaptic currents. Our approach provides rigorous quantitative tools for the analysis of synaptic events in mouse models of disease for objectively and reliably revealing even subtle disease-related alterations.