All ETDs from UAB

Advisory Committee Chair

Lucas Pozzo-Miller

Advisory Committee Members

Cristin F Gavin

Gwendalyn D King

Stephen A Watts

Document Type

Thesis

Date of Award

2019

Degree Name by School

Master of Science (MS) College of Arts and Sciences

Abstract

Rett syndrome (RTT) is a neurodevelopmental disorder representing the second most common cause of intellectual disability in women. Most RTT cases are caused by mutations in the gene coding for the transcriptional regulator Methyl-CpG-binding Protein 2 (MeCP2). The neurotrophin BDNF (Brain-Derived Neurotrophic Factor) has therapeutic potential for RTT because BDNF levels are lower in RTT autopsy brains and in Mecp2 deficient mice, while conditional Bdnf deletion results in phenotypes similar to those of Mecp2 knockout (KO) mice. In addition, Bdnf overexpression in forebrain excitatory neurons in Mecp2 KO mice significantly improved their lifespan, locomotor function, and brain weight. However, BDNF has low blood-brain barrier permeability and potential undesired effects by activation of the p75 neurotrophin receptor. Prompted by these limitations, a search for small molecule mimetics of the BDNF loop domain yielded the compound LM22A-4, which selectively activates the BDNF receptor TrkB. LM22A-4 improves respiratory function, object location memory, and hippocampal synaptic plasticity in female Mecp2 heterozygous (HET) mice. Recently, our lab reported social memory deficits and atypical social behaviors in male Mecp2 KO mice. To expand on these findings, we tested whether female Mecp2 HET mice exhibit similar deficits, with the aim of testing improvement by a 4-week treatment with LM22A-4. In this study, all mice were tested in two social interactions tasks: a novel Unrestricted Social Interaction assay and the standard Three-Chamber social test. We found that female Mecp2 HET mice display RTT-like disease progression, with four-month-old mice exhibiting transient atypical social behaviors not observed in six-month-old mice, and the worsening of two other behaviors: increased time in repetitive stereotypy-like digging and fear-induced shuffling. LM22A-4 also reduced the atypical repetitive digging behavior in female Mecp2 HET mice, reaching levels observed in female wild-type mice. However, LM22A-4 did not affect social behaviors in both genotypes. Overall, these results define a set of behavioral deficits that occur transiently during disease progression in female Mecp2 HET mice, and others that progress with a slower time course. In addition, LM22A-4 decreased atypical repetitive behaviors in female Mecp2 HET mice, without affecting typical behaviors in female wild-type mice, underscoring its potential therapeutic value.

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