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Soutenance de thèse – Celeste Ferraguto

Name: Soutenance de thèse – Celeste Ferraguto
Start: 2024-07-09T14:00:00+02:00
End: 2024-07-09T14:00:00+02:00

Tuesday 9 July / 14:00

Venue: centre Broca

Defense in french

Celeste Ferraguto
Team: “MEMORY”, INCIA

Supervisor: Susanna Pietropaolo

Title

BKCa channels as therapeutic targets in neurodevelopmental disorders: focus on acoustic dysfunction

Abstract

Neurodevelopmental disorders (NDDs) are typically characterized by a range of pathological phenotypes, encompassing a variety of physical, brain and behavioral abnormalities. Among these, impaired auditory perception and hearing alterations are commonly observed across multiple NDDs. Given the presence of a shared symptomatology, increasing interest is devoted to the identification of potential common underlying mechanisms and, therefore, shared therapeutic strategies. Despite extensive efforts, effective pharmacological interventions for most NDDs are still lacking, prompting research on novel drugs, as well as on repurposed treatments. Dysfunction in big conductance calcium-activated potassium (BKCa) ion channels has emerged as a potential key pathological mechanism involved in multiple NDDs: these ubiquitous channels play a pivotal role in modulating the activity of excitable cells, including neurons, vascular smooth-muscle and cardiac cells, as well as cochlear hair cells, thus being strongly implicated in synaptic, cardio-vascular and auditory functions. Notably, reduced expression and functionality of BKCa channels have been documented in patients with two major NDDs, i.e., fragile X and Williams-Beuren syndromes (FXS and WBS), suggesting that compounds activating these channels could offer promising treatments for these two genetic syndromes. This thesis aimed to provide preclinical evidence supporting the therapeutic potential of chlorzoxazone, an FDA-approved BKCa channel opener, for treating the pathological phenotypes of FXS and WBS. To this end, we employed the Fmr1-KO and the CD mouse lines, representing the main preclinical models of FXS and WBS, respectively, which recapitulate most symptoms displayed by patients, including BKCa channel expression and functional deficits. In the first part of the thesis, we demonstrated that chlorzoxazone, administered either acutely or chronically, effectively treated various behavioral, brain, and physical phenotypes exhibited by Fmr1-KO and CD mutants. To this aim, we combined behavioral assessments of both mutant mouse lines, encompassing motor, emotional, and social tests, with the analysis of markers of neuronal plasticity and functionality markers, e.g., dendritic abnormalities, neurotrophin levels, and fos expression in specific brain regions. Additionally, in the CD mouse model, we characterized cardiovascular phenotypes typical of WBS, i.e., cardiac hypertrophy and aortic stenosis. In the second part, we focused on the auditory alterations displayed by the two mouse models and we showed the overall efficacy of chlorzoxazone in rescuing these abnormalities at electrophysiological, structural, and behavioral levels. This involved assessing auditory brainstem responses and distortion product otoacoustic emissions, alongside the immuno-histochemical evaluation of cochlear hair cells and ribbon synapses, and behavioral analysis of the acoustic startle response. Overall, our findings support BKCa channels as promising therapeutic targets for FXS and WBS, as well as for associated auditory dysfunctions. Furthermore, they advocate for repurposing chlorzoxazone, already on the market for muscular pathologies, for clinical use in the context of NDDs. In conclusion, this thesis provides a preclinical foundation for future clinical trials in FXS and WBS, and encourages further preclinical research into the role of BKCa channels in auditory and behavioral dysfunction.

Keywords: Neurodevelopmental disorders, BKCa channels, auditory impairments, genetic mouse models, pharmacology, mouse behaviour

Publications

C. Ferraguto, Y. Bouleau, T. Peineau, D. Dulon, S. Pietropaolo. Hyperacusis in the Adult Fmr1-KO Mouse Model of Fragile X Syndrome: The Therapeutic Relevance of Cochlear Alterations and BKCa Channels. Int J Mol Sci. 2023 Jul 24;24(14):11863. doi: 10.3390/ijms241411863.

S. Giannoccaro*, C. Ferraguto*, V. Petroni, C. Marcelly, X. Nogues, V. Campuzano, S.Pietropaolo. Early Neurobehavioral Characterization of the CD Mouse Model of Williams-Beuren Syndrome. Cells. 2023 Jan 21;12(3):391. doi: 10.3390/cells12030391. * equal contribution

I. Del Pino, C.Tocco, E. Magrinelli, A. Marcantoni, C. Ferraguto, G. Tomagra, M. Bertacchi, C. Alfano, X.Leinekugel, A. Frick, M. Studer. COUP-TFI/Nr2f1 Orchestrates Intrinsic Neuronal Activity during Development of the Somatosensory Cortex. Cereb Cortex. 2020 Oct 1;30(11):5667-5685. doi: 10.1093/cercor/bhaa137.