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

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 APPNL-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 APPNL-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 APPNL-F/NL-F mice. These effects exacerbated synaptic hyperactivity reported previously in the APPNL-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

TMT-based quantitative proteomics reveals that electroacupuncture has neuroprotective effect on Alzheimer's disease rats through synaptic vesicle cycle and glutamatergic synapse signal pathways

“…Studies have con rmed signi cantincreased GAT3/4 expression in astrocytes in hippocampus of APP knockout mouse model along with the enhancement of tonic inhibition [22].The excessive GABA and GABA transporter GAT3/4 was also observed in 5xFAD mouse model, and signi cantly enhanced tonic GABA inhibition and memory de cits in reactive astrocytes in the dentate gyrus (DG) of the hippocampus [23]. According to our TMT results, we con rmed that the upregulation of GAT3.…”

GABA Release from Astrocytes in Health and Disease

“…Thus, in the hippocampus of the 5xFAD mouse model of AD, both GABA synthesis and release via GAT3 are specifically facilitated in reactive astrocytes, but not in neurons [28]. Similar results were obtained in another model of AD, the APP NL−F/NL−F knock-in mouse model [91]. Moreover, in this case, both GABA content and GAD67 expression are significantly increased in reactive astrocytes, leading to the GAT3-mediated GABA release and increased tonic inhibition of principal neurons in the CA1 and DG regions of the hippocampus [91].…”

“…[35] reported that the Best1 silencing by means of shRNA blocks GABA release in the 5xFAD AD mouse model as well, which also suggests the Best1-mediated GABA release in this AD mouse model. These results contradict the GAT3-mediated release reported by Wu et al and Aldabbagh et al [28,91]. Unfortunately, this contradiction was not discussed in this publication.…”

“…Similar results were obtained in another model of AD, the APP NL−F/NL−F knock-in mouse model [91]. Moreover, in this case, both GABA content and GAD67 expression are significantly increased in reactive astrocytes, leading to the GAT3-mediated GABA release and increased tonic inhibition of principal neurons in the CA1 and DG regions of the hippocampus [91]. Unfortunately, the expression of Best1 channel has not been inspected in these publications.…”

The fate of interneurons, GABAA receptor sub‐types and perineuronal nets in Alzheimer's disease

“…Alzheimer's disease (AD) is the most common form of dementia and neurodegenerative condition in humans, with close to two‐thirds of all patients diagnosed with dementia being attributed to the onset of the disorder [ 1 ]. The cellular hallmarks of AD including, increased levels of both amyloid β (Aβ) deposition and neurofibrillary tangle formation, play an important function in activating neuroprotective mechanisms originating from both microglia and astrocytes, which after a certain point, begin to contribute towards the development of the pathogenesis associated with AD [ 2 , 3 ]. A consistent phenotype of AD that spans from human studies to various rodent models of AD is the abnormal synaptic hyperexcitation preceding phenotypic alteration of the disease, which has been noted as a relevant therapeutic target [ 4 , 5 , 6 ].…”