Open AccessEffects of α5 GABA A receptor modulation on social interaction, memory, and neuroinflammation in a mouse model of Alzheimer's disease
Author(s) -
Aranđelović Jovana,
Santrač Anja,
Batinić Bojan,
Todorović Lidija,
Stevanović Vladimir,
Tiruveedhula Veera Venkata Naga Phani Babu,
Sharmin Dishary,
Rashid Farjana,
Stanojević Boban,
Cook James M.,
Savić Miroslav M.
Publication year - 2022
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.13914
Subject(s) - neuroinflammation , transgene , genetically modified mouse , hippocampus , neuroscience , gabaergic , psychology , medicine , biology , disease , biochemistry , gene , inhibitory postsynaptic potential
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.