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Preserved Calretinin interneurons in an app model of Alzheimer’s Disease disrupts hippocampal inhibition via up-regulated P2Y1 purinoreceptors

Shi, A; Petrache, AL; Shi, J; Ali, A; (2020) Preserved Calretinin interneurons in an app model of Alzheimer’s Disease disrupts hippocampal inhibition via up-regulated P2Y1 purinoreceptors. Cerebral Cortex , 30 (3) pp. 1272-1290. 10.1093/cercor/bhz165. Green open access

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Abstract

To understand the pathogenesis of specific neuronal circuit dysfunction in Alzheimer’s disease (AD), we investigated the fate of three subclasses of “modulatory interneurons” in hippocampal CA1 using the App^{NL-F/NL-F} knock-in mouse model of AD. Cholecystokinin- and somatostatin-expressing interneurons were aberrantly hyperactive preceding the presence of the typical AD hallmarks: neuroinflammation and amyloid-β (Aβ) accumulation. These interneurons showed an age-dependent vulnerability to Aβ penetration and a reduction in density and coexpression of the inhibitory neurotransmitter GABA synthesis enzyme, glutamic acid decarboxylase 67 (GAD67), suggesting a loss in their inhibitory function. However, calretinin (CR) interneurons—specialized to govern only inhibition, showed resilience to Aβ accumulation, preservation of structure, and displayed synaptic hyperinhibition, despite the lack of inhibitory control of CA1 excitatory pyramidal cells from midstages of the disease. This aberrant inhibitory homeostasis observed in CA1 CR cells and pyramidal cells was “normalized” by blocking P2Y1 purinoreceptors, which were “upregulated” and strongly expressed in CR cells and astrocytes in App^{NL-F/NL-F} mice in the later stages of AD. In summary, AD-associated cell-type selective destruction of inhibitory interneurons and disrupted inhibitory homeostasis rectified by modulation of the upregulated purinoreceptor system may serve as a novel therapeutic strategy to normalize selective dysfunctional synaptic homeostasis during pathogenesis of AD.

Type: Article
Title: Preserved Calretinin interneurons in an app model of Alzheimer’s Disease disrupts hippocampal inhibition via up-regulated P2Y1 purinoreceptors
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/cercor/bhz165
Publisher version: https://doi.org/10.1093/cercor/bhz165
Language: English
Additional information: © The Author(s) 2019. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/).
Keywords: Alzheimer’s disease, interneurons, astrocytes, synapse, P2Y1 receptors
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/10078133
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