Effects of α5 GABAA receptor modulation on social interaction, memory, and neuroinflammation in a mouse model of Alzheimer's disease

Jovana Aranđelović; Anja Santrač; Bojan Batinić; Lidija Todorović; Vladimir Stevanović; Veera Venkata Naga Phani Babu Tiruveedhula; Dishary Sharmin; Farjana Rashid; Boban Stanojević; James M Cook; Miroslav M Savić

doi:10.1111/cns.13914

Effects of α5 GABA_A receptor modulation on social interaction, memory, and neuroinflammation in a mouse model of Alzheimer's disease

CNS Neurosci Ther. 2022 Nov;28(11):1767-1778. doi: 10.1111/cns.13914. Epub 2022 Jul 13.

Affiliations

¹ Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
² Department of Physiology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
³ Laboratory for Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences, National Institute of thе Republic of Serbia, University of Belgrade, Belgrade, Serbia.
⁴ Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, USA.
⁵ Comprehensive Cancer Centre, Faculty of Life Sciences & Medicine, King's College London, Rayne Institute, London, UK.

Abstract

Aims: GABAergic modulation involved in cognitive processing appears to be substantially changed in Alzheimer's disease (AD). In a widely used 5xFAD model of AD, we aimed to assess if negative and positive allosteric modulators of α5 GABA_A receptors (NAM and PAM, respectively) would affect social interaction, social, object and spatial memory, and neuroinflammation.

Methods: After 10-day treatment with PAM, NAM, or solvent, 6-month-old transgenic and non-transgenic 5xFAD mice underwent testing in a behavioral battery. Gene expressions of IL-1β, IL-6, TNF-α, GFAP, and IBA-1 were determined in hippocampus and prefrontal cortex by qPCR.

Results: PAM treatment impaired spatial learning in transgenic females compared to solvent-treated transgenic females, and social recognition in transgenic and non-transgenic males. NAM treatment declined social interaction in transgenic and non-transgenic males, while had beneficial effect on cognitive flexibility in non-transgenic males compared to solvent-treated non-transgenic males. Transgenic animals have not fully displayed cognitive symptoms, but neuroinflammation was confirmed. NAM reduced proinflammatory gene expressions in transgenic females and astrogliosis in transgenic males compared to pathological controls.

Conclusion: PAM and NAM failed to exert favorable behavioral effects in transgenic animals. Suppression of neuroinflammation obtained with NAM calls for more studies with GABAergic ligands in amyloid beta- and/or tau-dependent models with prominent neuroinflammation.

Keywords: 5xFAD; Alzheimer's disease; cognition; neuroinflammation; α5 GABAA receptor modulation.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural

MeSH terms

Alzheimer Disease* / drug therapy
Alzheimer Disease* / genetics
Alzheimer Disease* / metabolism
Amyloid beta-Peptides / metabolism
Animals
Disease Models, Animal
Female
Interleukin-6 / metabolism
Male
Memory
Mice
Mice, Transgenic
Neuroinflammatory Diseases
Receptors, GABA-A / genetics
Social Interaction
Solvents
Tumor Necrosis Factor-alpha / metabolism
gamma-Aminobutyric Acid

Substances

Amyloid beta-Peptides
Interleukin-6
Receptors, GABA-A
Solvents
Tumor Necrosis Factor-alpha
gamma-Aminobutyric Acid

Grants and funding

R01 NS076517/NS/NINDS NIH HHS/United States