Impaired In Vivo Gamma Oscillations in the Medial Entorhinal Cortex of Knock-in Alzheimer Model.

Tomoaki Nakazono,Masashi Kitazawa,Takashi Saito,Travis N Lam,Ayushi Y Patel,Kei M Igarashi,Takaomi C Saido

doi:10.3389/fnsys.2017.00048

Abstract

The entorhinal cortex (EC) has bidirectional connections with the hippocampus and plays a critical role in memory formation and retrieval. EC is one of the most vulnerable regions in the brain in early stages of Alzheimer’s disease (AD), a neurodegenerative disease with progressive memory impairments. Accumulating evidence from healthy behaving animals indicates gamma oscillations (30–100 Hz) as critical for mediating interactions in the circuit between EC and hippocampus. However, it is still unclear whether gamma oscillations have causal relationship with memory impairment in AD. Here we provide the first evidence that in vivo gamma oscillations in the EC are impaired in an AD mouse model. Cross-frequency coupling of gamma (30–100 Hz) oscillations to theta oscillations was reduced in the medial EC of anesthetized amyloid precursor protein knock-in (APP-KI) mice. Phase locking of spiking activity of layer II/III pyramidal cells to the gamma oscillations was significantly impaired. These data indicate that the neural circuit activities organized by gamma oscillations were disrupted in the medial EC of AD mouse model, and point to gamma oscillations as one of possible mechanisms for cognitive dysfunction in AD patients.

Highlights

The entorhinal cortex (EC) plays a critical role in the formation of declarative memory (Van Hoesen et al, 1991; Gomez-Isla et al, 1996)
Our results indicate the temporal organization between theta and gamma oscillations, and temporal structure between spikes of layer II/III pyramidal cells and gamma oscillation were both disrupted in amyloid precursor protein knock-in (APP-KI) mice
We showed that theta-gamma cross-frequency coupling and gamma phase locking of MEC layer II/III pyramidal cells were impaired in amyloid precursor protein (APP)-KI mice, as compared with age-matched WT mice

Summary

Introduction

The entorhinal cortex (EC) plays a critical role in the formation of declarative memory (Van Hoesen et al, 1991; Gomez-Isla et al, 1996). Information encoded in MEC is sent to hippocampal CA1 via temporoammonic pathway, and to CA3/dentate gyrus via performant pathway, providing spatial information to these regions (Witter et al, 2000). Accumulating evidence suggests EC as one of the focal sites of disease progression in Alzheimer’s disease (AD), a neurodegenerative disease in which accumulation of amyloid-β (Aβ) and tau leads to synaptic, network and cognitive dysfunctions; In AD patients, the EC shows severe atrophy, with neuronal loss and dense Aβ accumulation (Hyman et al, 1984; Van Hoesen et al, 1991; Gomez-Isla et al, 1996). A recent study reported reduced MEC grid cell activity in an animal model of AD

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