FILIZ, K.D. (2024) Synaptic Impairments in Autism Spectrum Disorder: Structural and Molecular Insights from Fmr1 KO and BTBR Models. [Tesi di dottorato]

Documento PDF Kardelen_Dalim_FILIZ_Ph.D_Thesis.pdf Visibile a [TBR] Amministratori dell'archivio Download (2MB) | Richiedi una copia

Abstract

Autism Spectrum Disorder (ASD) is a multifaceted neurodevelopmental disorder marked by a wide range of social, communicative, and behavioral impairments. Emerging evidence suggests that alterations in synaptic structure and function, particularly involving dendritic spine morphology and serotonin signaling, contribute significantly to the pathophysiology of ASD. In this study, we investigated synaptic alterations in two ASD models: Fmr1 KO mice, representing Fragile X Syndrome, and BTBR mice, an idiopathic model of ASD. Our group developed a novel approach combining DiIC18 staining with immunofluorescence, allowing for precise analysis of dendritic spine morphology and protein distribution. In juvenile Fmr1 KO mice hippocampi, our technique revealed an increased spine density, a significant reduction in mature mushroom-shaped spines, and an increase in immature elongated spines, highlighting synaptic instability. The ability to visualize Synaptopodin-positive mushroom spines further underscored impairments in synaptic architecture and maturation. In adult BTBR mice cortices, we observed an increased dendritic spine density, predominantly immature spines, indicative of abnormal synaptic development. Molecular analyses of synaptosomal fractions from juvenile BTBR mice cortices revealed a downregulation of the 5-HT7 receptor (5-HT7R), suggesting impaired serotonin signaling as a contributor to synaptic dysfunction. Treatment with the 5-HT7R agonist LP-211 successfully restored synaptic protein synthesis, demonstrating its potential as a therapeutic target for addressing synaptic dysfunctions associated with ASD. These findings provide critical insights into the synaptic mechanisms underlying ASD, while the development of a combined DiIC18-immunofluorescence technique offers an advanced tool for studying synaptic architecture. The modulation of 5-HT7R presents a promising therapeutic strategy, opening new avenues for targeted interventions in ASD.

Downloads

Actions (login required)

Modifica documento