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

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

Constructing a Time-Invariant Measure of the Socio-economic Status of U.S. Census Tracts

Contextual research on time and place requires a consistent measurement instrument for neighborhood conditions in order to make unbiased inferences about neighborhood change. We develop such a time-invariant measure of neighborhood socio-economic status (NSES) using exploratory and confirmatory factor analyses fit to census data at the tract level from the 1990 and 2000 U.S. Censuses and the 2008–2012 American Community Survey. A single factor model fit the data well at all three time periods, and factor loadings—but not indicator intercepts—could be constrained to equality over time without decrement to fit. After addressing remaining longitudinal measurement bias, we found that NSES increased from 1990 to 2000, and then—consistent with the timing of the “Great Recession”—declined in 2008–2012 to a level approaching that of 1990. Our approach for evaluating and adjusting for time-invariance is not only instructive for studies of NSES but also more generally for longitudinal studies in which the variable of interest is a latent construct