Early restoration of parvalbumin interneuron activity prevents memory loss and network hyperexcitability in a mouse model of Alzheimer’s disease

Sara Hijazi, Tim S. Heistek, Philip Scheltens, Ulf Neumann, Derya R. Shimshek, Huibert D. Mansvelder, August B. Smit, Ronald E. van Kesteren*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Neuronal network dysfunction is increasingly recognized as an early symptom in Alzheimer’s disease (AD) and may provide new entry points for diagnosis and intervention. Here, we show that amyloid-beta-induced hyperexcitability of hippocampal inhibitory parvalbumin (PV) interneurons importantly contributes to neuronal network dysfunction and memory impairment in APP/PS1 mice, a mouse model of increased amyloidosis. We demonstrate that hippocampal PV interneurons become hyperexcitable at ~16 weeks of age, when no changes are observed yet in the intrinsic properties of pyramidal cells. This hyperexcitable state of PV interneurons coincides with increased inhibitory transmission onto hippocampal pyramidal neurons and deficits in spatial learning and memory. We show that treatment aimed at preventing PV interneurons from becoming hyperexcitable is sufficient to restore PV interneuron properties to wild-type levels, reduce inhibitory input onto pyramidal cells, and rescue memory deficits in APP/PS1 mice. Importantly, we demonstrate that early intervention aimed at restoring PV interneuron activity has long-term beneficial effects on memory and hippocampal network activity, and reduces amyloid plaque deposition, a hallmark of AD pathology. Taken together, these findings suggest that early treatment of PV interneuron hyperactivity might be clinically relevant in preventing memory decline and delaying AD progression.

Original languageEnglish
Pages (from-to)3380-3398
Number of pages19
JournalMolecular Psychiatry
Volume25
Issue number12
Early online date20 Aug 2019
DOIs
Publication statusPublished - Dec 2020

Funding

Acknowledgements We thank Rolinka van der Loo and Nina Straat for technical assistance and Harry Twaalfhoven for performing the ELISA experiments. SH received funding from the EU-FP7-PEOPLE program (CognitionNet; grant 607508). REvK received funding from the Dutch Alzheimer Association (Alzheimer Nederland; grant WE.03-2017-03).

FundersFunder number
Dutch Alzheimer AssociationWE.03-2017-03
Not added607508

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