Alzheimer's Disease Enhanced Tonic Inhibition is Correlated With Upregulated Astrocyte GABA Transporter-3/4 in a Knock-In APP Mouse Model.

Yousif Aldabbagh,Weicong Zhang,Afia B Ali,Anam Islam,Paul Whiting

doi:10.3389/fphar.2022.822499

Abstract

Cognitive decline is a major symptom in Alzheimer’s disease (AD), which is strongly associated with synaptic excitatory-inhibitory imbalance. Here, we investigated whether astrocyte-specific GABA transporter 3/4 (GAT3/4) is altered in APP knock-in mouse model of AD and whether this is correlated with changes in principal cell excitability. Using the APP NL-F/NL-F knock-in mouse model of AD, aged-matched to wild-type mice, we performed in vitro electrophysiological whole-cell recordings combined with immunohistochemistry in the CA1 and dentate gyrus (DG) regions of the hippocampus. We observed a higher expression of GAD67, an enzyme that catalyses GABA production, and GAT3/4 in reactive astrocytes labelled with GFAP, which correlated with an enhanced tonic inhibition in the CA1 and DG of 12–16 month-old APP NL-F/NL-F mice compared to the age-matched wild-type animals. Comparative neuroanatomy experiments performed using post-mortem brain tissue from human AD patients, age-matched to healthy controls, mirrored the results obtained using mice tissue. Blocking GAT3/4 associated tonic inhibition recorded in CA1 and DG principal cells resulted in an increased membrane input resistance, enhanced firing frequency and synaptic excitation in both wild-type and APP NL-F/NL-F mice. These effects exacerbated synaptic hyperactivity reported previously in the APP NL-F/NL-F mice model. Our data suggest that an alteration in astrocyte GABA homeostasis is correlated with increased tonic inhibition in the hippocampus, which probably plays an important compensatory role in restoring AD-associated synaptic hyperactivity. Therefore, reducing tonic inhibition through GAT3/4 may not be a good therapeutic strategy for AD

Highlights

Alzheimer’s disease (AD) is the most prevalent cause of dementia in the elderly, affecting 6–8% of the world’s population over 65 years old (WHO, 2017)
We stained for astrocyte specific gliotransmitters such as ?-aminobutyric acid (GABA) transporter, GABA transporter 3/4 (GAT3/4), to investigate the anatomical changes of astrocytes in AD
This study reveals novel data concerning the possible role of the GABA transporter GAT3/4 in AD, and provides a mechanistic insight into the pathophysiology of AD in terms of synaptic imbalance governed by astrocyte-specific mechanisms that contribute to altered background tonic inhibition in the first knock-in APPNL-F/NL-F mouse model of AD

Summary

Introduction

Alzheimer’s disease (AD) is the most prevalent cause of dementia in the elderly, affecting 6–8% of the world’s population over 65 years old (WHO, 2017). AD is a progressive disorder that leads to cognitive deficits which severely reduce quality of life (Burns and Iliffe, 2009), and is described macroscopically by loss of brain volume and shrinkage of cortical gyri, with the entorhinal cortex and hippocampus being heavily affected (Stelzma et al, 1995). The major pathological hallmarks of AD are neuroinflammation, presence of severe neuropathological lesions, including amyloid-β (Aβ) plaques, synaptic loss, and neuronal death. Recent studies have shown that Aβ-induced dysfunction of astrocytes networks can lead to dysregulated neuronal networks and a positive feedback loop with Aβ formation and deposition; with similar effects not seen in the non-pathological ageing brain (Gómez-Gonzalo et al, 2017; Lines et al, 2022)

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