Advisor(s)
Lucas Pozzo-Miller
Committee Member(s)
Andrew Hardaway
Karen Gamble
Kirstie Cummings
Sage Aronson
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Neurobiology
Date of Award
1-7-2025
Abstract
Rett syndrome (RTT) is a neurodevelopmental disorder primarily affecting females, caused by pathogenic variants in the X-linked MECP2 gene, which encodes the transcriptional modulator Methyl-CpG binding protein 2 (MeCP2). RTT is characterized by motor deficits, loss of speech, autistic features, and intellectual disability. A key gene regulated by MeCP2 is BDNF, encoding the neurotrophin brain-derived neurotrophic factor (BDNF). BDNF levels are lower in multiple brain regions of Mecp2-deficient mice, and experimentally increasing BDNF levels improves several RTT phenotypes in mouse models. Due to BDNF's low blood-brain barrier permeability, we tested LM22A-4, a brain-penetrant small molecule ligand of TrkB receptors, on dendritic spine density and behavioral phenotypes in female Mecp2 heterozygous (HET) mice. We validated LM22A-4's therapeutic effect on dendritic spine dysgenesis in organotypic hippocampal slices from Mecp2 KO mice. Subsequently, we tested systemic LM22A-4 treatment in Mecp2 HET mice and found it reduced the enlarged volume of CA1 dendritic spines in MeCP2-expressing neurons to wildtype (WT) levels, while MeCP2-lacking neurons remained unchanged. We tested LM22A-4's effects on social behaviors in female Mecp2 HET mice, focusing on autism spectrum disorders (ASD)- related phenotypes, including sociability, social memory, and naturalistic behaviors. LM22A-4 did not mitigate the delayed social memory phenotype observed in Mecp2 HET mice during the 3-chamber social interaction test. However, in an unrestricted social assay, LM22A-4 reduced aggressive behaviors in Mecp2 HET mice to WT levels. Social memory impairments in Mecp2 KO mice result from altered neuronal activity in the monosynaptic projection from the ventral hippocampus (vHIP) to the medial prefrontal cortex (mPFC). Using a 4-chamber social arena with fiber photometry, we found mPFC pyramidal neurons (PYRs) activity in Mecp2 KO mice was unchanged during toy or cage-mate explorations but was desynchronized during novel mouse interactions. Contrastingly, WT mice showed specific increases in parvalbumin interneurons (PV-IN) activity during cage-mate interactions, while Mecp2 KO mice displayed desynchronized activity before familiar mouse interactions. Our findings highlight LM22A-4's potential in addressing dendritic spine dysgenesis and atypical behaviors in RTT. This work underscores MeCP2's crucial role in maintaining proper neuronal activity during social interactions, offering insights for targeted therapies in RTT and ASD.
ProQuest ID
Recommended Citation
Medeiros, Destynie, "Insights Into Rett Syndrome: Social Behavior, Bdnf-Trkb Signaling, And Dendritic Spines" (2025). All ETDs from UAB. 7247.
https://digitalcommons.library.uab.edu/etd-collection/7247
