Abstract
In Alzheimer’s disease (AD) the accumulation of amyloid-β (Aβ) correlates with degradation of cognition-relevant gamma oscillations. The gamma rhythm relies on proper neuronal spike-gamma coupling, specifically of fast-spiking interneurons (FSN). Here we tested the hypothesis that decrease in gamma power and FSN synchrony precede amyloid plaque deposition and cognitive impairment in AppNL-G-F knock-in mice (AppNL-G-F). The aim of the study was to evaluate the amyloidogenic pathology progression in the novel AppNL-G-F mouse model using in vitro electrophysiological network analysis. Using patch clamp of FSNs and pyramidal cells (PCs) with simultaneous gamma oscillation recordings, we compared the activity of the hippocampal network of wild-type mice (WT) and the AppNL-G-F mice at four disease stages (1, 2, 4, and 6 months of age). We found a severe degradation of gamma oscillation power that is independent of, and precedes Aβ plaque formation, and the cognitive impairment reported previously in this animal model. The degradation correlates with increased Aβ1-42 concentration in the brain. Analysis on the cellular level showed an impaired spike-gamma coupling of FSN from 2 months of age that correlates with the degradation of gamma oscillations. From 6 months of age PC firing becomes desynchronized also, correlating with reports in the literature of robust Aβ plaque pathology and cognitive impairment in the AppNL-G-F mice. This study provides evidence that impaired FSN spike-gamma coupling is one of the earliest functional impairment caused by the amyloidogenic pathology progression likely is the main cause for the degradation of gamma oscillations and consequent cognitive impairment. Our data suggests that therapeutic approaches should be aimed at restoring normal FSN spike-gamma coupling and not just removal of Aβ.
Highlights
Alzheimer’s disease (AD) is the main cause of dementia and a major health concern for society
For the last time point (6 m.o.), for which a robust amyloid-β peptide (Aβ) plaque load as well as cognitive impairment is reported in AppNL-G-F mice [30,31,32], we found a significant decrease of gamma oscillation power (p = 0.0006; Fig. 1b, c) and an increase in frequency variance (p = 0.0051; Fig. 1d, e)
Impaired fast-spiking interneurons (FSN) spike-gamma coupling in AppNL-G-F mice appears at 2 months of age In our previous work, we have shown that Aβ acutely impairs the spike-gamma coupling of pyramidal cells (PC) and FSNs leading to degradation of gamma oscillations in WT mice [4, 21, 41]
Summary
Alzheimer’s disease (AD) is the main cause of dementia and a major health concern for society. Gamma oscillations are well described in different brain regions and are known to act as a temporal scaffold for neuronal communication and information processing [10]. Gamma oscillations are the result of the rhythmic synchronization of action potentials generated by excitatory pyramidal cells (PC) and inhibitory fast-spiking interneurons (FSN), and the resultant rhythmic postsynaptic currents. These currents can be recorded macroscopically in electroencephalograms, or invasively as local field potentials (LFP) [7, 10]. The close communication with the dentate gyrus establishes a local circuitry involved in episodic memory [15,16,17]
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