Positive and Negative Selective Allosteric Modulators of α5 GABAA Receptors: Effects on Emotionality, Motivation, and Motor Function in the 5xFAD Model of Alzheimer’s Disease

Abstract

Background: Positive and negative allosteric modulators of α5 GABAA receptors (PAM and NAM, respectively) are worthy of investigation as putative treatments of Alzheimer’s disease (AD). However, their potential to modify a dynamic range of behaviors in AD models needs to be systematically examined. Objective: The study aimed to assess effects of MP-III-022 as PAM and PWZ-029 as NAM on emotional reactivity, motivation, and motor function, as well as on gene expression of GABRA2, GABRA3 and GABRA5 subunit of GABAA receptors in prefrontal cortex (PFC) and hippocampus (HC) in 5xFAD mice, as an early-onset transgenic AD model. Methods: The 6-month-old 5xFAD transgenic and non-transgenic mice of both genders underwent a battery of reflexes and behavioral tests (sensorimotor tests, elevated plus maze, and open field) after 10-day intraperitoneal treatment with MP-III-022, PWZ-029, or solvent. The behavioral battery was followed by qPCR analysis of gene expression. Results: MP-III-022 induced a decline in motor function, while PWZ-029 further decreased emotionality of transgenic males, as compared to the transgenic control. No interfering effects on non-cognitive behavior were observed in female mice. In HC, both treatments reversed reciprocal GABRA2 and GABRA3 changes in transgenic females. In PFC, MP-III-022 decreased GABRA5 in both genders, while PWZ-029 increased GABRA2 in male transgenic animals. Conclusion: Gender-dependent protracted effects of PAMs and NAMs in AD model, with detrimental impact on motor capabilities of PAM, and attenuation of emotionality elicited by NAM in transgenic males, were revealed. This favors future research of α5 GABAA receptor modulation in females as more promising.

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

“…All aforementioned evidence indicates that the lack of clear-cut opposite effects of the selected PAM and NAM tested in this and previous study 28 was far from unexpected. Moreover, the PAM and NAM effects were strongly dependent on the experimental group, and could be similar, opposite, or neutral.…”

“…In transgenic females, MP‐III‐022 treatment led to an increased peripheral time in the probe test and thus probably had a negative impact on procedural component of acquisition, as expected for positive modulation of α5 GABA A receptors. 44 On the other hand, transgenic male and female controls, in line with their behavior in the elevated plus maze and open field, 28 had decreased emotional reactivity, manifested as less time spent in the thigmotaxic zone compared to their healthy controls in reversal probe and probe test, respectively. However, both ligand treatments, compared to solvent, were apparently linked with decreased anxiety in reversal probe in non‐transgenic males, as reflected in lower peripheral time.…”

“…treatment with MP‐III‐022, PWZ‐029 or SOL during 10 days at 6 months ±2 weeks of age. After completing the treatment protocol, each animal subcohort underwent a behavioral battery comprised of tests for sensory and motor abilities, elevated plus maze, open field (the results published in 28 ), novel object recognition test, three‐chamber test, and Morris water maze test (Figure 1). Hence, all animals were subjected to the same experimental procedure under considerably similar conditions, but divided in three time points, which is relevant for increasing reproducibility of this study 29 .…”

“…Timeline of behavioral battery conducted on each 5xFAD animal cohort treated with MP‐III‐022, PWZ‐029, or solvent. Red text signifies experiments analyzed and discussed in this manuscript, while tests without coloring have been already published 28 . Abbreviations: 3 CT, three‐chamber test; EPM, elevated plus maze; MWM, Morris water maze; NORT, novel object recognition test; OF, open field…”