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

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 alpha 5 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-1 beta, IL-6, TNF-alpha, 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.

Automated summary

The aim of this study was to assess the effects of negative and positive allosteric modulators of alpha 5 GABA(A) receptors on behavior and neuroinflammation in a widely used Alzheimer's disease (AD) model. The results showed that these modulators had some effects on the behavior and neuroinflammation of transgenic mice, but did not achieve the expected beneficial effects.