Aberrant Excitatory-Inhibitory Synaptic Mechanisms in Entorhinal Cortex Microcircuits During the Pathogenesis of Alzheimer's Disease.

Anqi Shi,Andrea Wetzel,Alexandra L Petrache,Kirsten Harvey,Afia B Ali,Takaomi C Saido,Takashi Saito,Aarib Rajulawalla

doi:10.1093/cercor/bhz016

Abstract

Synaptic dysfunction is widely proposed as an initial insult leading to the neurodegeneration observed in Alzheimer’s disease (AD). We hypothesize that the initial insult originates in the lateral entorhinal cortex (LEC) due to deficits in key interneuronal functions and synaptic signaling mechanisms, in particular, Wnt (Wingless/integrated). To investigate this hypothesis, we utilized the first knock-in mouse model of AD (AppNL-F/NL-F), expressing a mutant form of human amyloid-β (Aβ) precursor protein. This model shows an age-dependent accumulation of Aβ, neuroinflammation, and neurodegeneration. Prior to the typical AD pathology, we showed a decrease in canonical Wnt signaling activity first affecting the LEC in combination with synaptic hyperexcitation and severely disrupted excitatory–inhibitory inputs onto principal cells. This synaptic imbalance was consistent with a reduction in the number of parvalbumin-containing (PV) interneurons, and a reduction in the somatic inhibitory axon terminals in the LEC compared with other cortical regions. However, targeting GABAA receptors on PV cells using allosteric modulators, diazepam, zolpidem, or a nonbenzodiazepine, L-838,417 (modulator of α2/3 subunit-containing GABAA receptors), restored the excitatory–inhibitory imbalance observed at principal cells in the LEC. These data support our hypothesis, providing a rationale for targeting the synaptic imbalance in the LEC for early stage therapeutic intervention to prevent neurodegeneration in AD.

Highlights

The axis between the entorhinal cortex and the hippocampus, important for the formation and consolidation of memories, is thought to be the first brain region to be significantly affected in patients with Alzheimer’s disease (AD), characterized by synaptic loss leading to neurodegeneration and progressive cognitive deficits (Palop et al 2006)
In the AppNL-F/NL-F mouse model, we observed age-dependent phenotypic changes of AD, including neuroinflammation indicated by astrocytosis, microgliosis and the progressive Aβ accumulation and deposition leading to plaque formation, which advocates progressive neurodegeneration, accurately recapitulating progression in AD patients
Using the first AD knock-in mouse model (AppNL-F/NL-F), which faithfully recapitulates disease progression in AD patients as shown by molecular studies (Saito et al 2014; Sasaguri et al 2017), we explored progressive changes in synaptic mechanisms underlying AD pathology in the lateral entorhinal cortex (LEC) with the following 3 key findings: firstly, we showed initial mechanistic synaptic dysfunction including a persistent hyperexcitation of pyramidal cell membrane properties and a diminished synaptic excitatory– inhibitory balance correlated with a reduction in canonical Wingless/ integrated (Wnt) signaling activity in the LEC

Summary

Introduction

The axis between the entorhinal cortex and the hippocampus, important for the formation and consolidation of memories, is thought to be the first brain region to be significantly affected in patients with Alzheimer’s disease (AD), characterized by synaptic loss leading to neurodegeneration and progressive cognitive deficits (Palop et al 2006). Postmortem AD brains present with amyloid-β (Aβ) plaques, neurofibrillary tangles, dystrophic neurites, and signs of neuroinflammation, including astrocytosis and gliosis (Holtzman et al 2011) Further to these contributors to the disease, deregulation of canonical Wingless/ integrated (Wnt) signaling, important for synaptic maintenance, has long been proposed as a key contributor to neurodegeneration including AD pathogenesis It has been shown that the observed hyperexcitability is initiated in the lateral entorhinal cortex (LEC) before it spreads to other cortical regions (Khan et al 2014) This abnormal hyperactivity is thought to be detrimental by causing Aβ release, spreading and accumulating during AD progression (Kamenetz et al 2003; Busche et al 2008; Cirrito et al 2008; Yamamoto et al 2015). This idea is further supported by studies reporting that a low dose of the antiepileptic drug levetiracetam can reduce hippocampal hyperactivity in humans and improve amnestic mild cognitive impairment (Bakker et al 2012)

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