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Thesis defense – William Fyke

17 March 2021 / 15:00

Defense is held behind closed doors

Title: Identifying Therapeutic Targets for the Treatment of Fragile X Syndrome: Implications for Autism Spectrum Disorder

Thesis supervisors: Susanna Pietropaolo (INCIA) and Juan Marcos Alarcon (SUNY Downstate Medical Center, Ney York)

Abstract: Fragile X syndrome (FXS) is a neurodevelopmental disorder due to an X-linked mutation in the FMR1 gene that results in intellectual disability (ID), autism spectrum disorder (ASD), anxiety, attention deficit hyperactivity disorder (ADHD) and sensory processing deficits. There is substantial overlap between FXS and ASD as approximately 30 to 50% of individuals diagnosed with FXS also meet the diagnostic criteria for ASD. Furthermore FXS-ASD patients represent approximately 5% of all cases of ASD. Since there is currently no targeted therapeutic approach, novel pharmacological agents addressing the neurobiological underpinnings of these disorders are crucially needed. Due to the overlap between the two conditions, systems which are disrupted in FXS and ASD patients may provide targets for treating the ASD symptoms observed in FXS-ASD patients and some non-syndromic ASD patients. FMRP, the protein lost by the FMR1 mutation, is a potent regulator of the endocannabinoid system (ECS) and BKCa channels. These function to regulate presynaptic excitability. Dysfunction in these systems is found in FXS patients and some ASD patients. The presynaptic role of these agents conceptualizes the “presynaptic hypothesis of FXS-ASD”. This project used genetic and pharmacological approaches which target FMRP, the ECS or BK_Ca channels in combination with an extensive behavioral characterization of FXS and ASD-relevant phenotypes, in order to assess the therapeutic value of these targets. This work demonstrates that the ECS and BKCa channels contribute to behavioral domains affected in neurodevelopmental disorders and offer several targets for therapeutics which should be explored.

Keywords: neurodevelopmental disorders, animal models, fragile x syndrome, autism spectrum disorder

Accepted Manuscripts

Fyke, W., Alarcon, J.M., Velinov, M., & Chadman, K.K. (2021) Pharmacological inhibition of BKCa channels induces a specific social deficit in adult C57BL6/J mice [Behavioral Neuroscience]

Manuscripts in review

Fyke, W., Alarcon, J.M., Velinov, M., & Chadman, K.K. (2021) Pharmacological inhibition of the primary endocannabinoid producing enzyme, DGL-α, induces ASD-like and co-morbid phenotypes in adult C57BL/J mice. [Autism Research]

Mendoza, R*. Fyke, W*., Daniel, D., Gabutan, E., Ballabh, D., Easy, M., Vasileva, A., Colbourn, R., Alawad, M., Dehghani, A., Lin, B., Emechebe, D., Patel, P., Jabbar, M., Nikolov, D. B., Giovaniello, D., Kang, S., Tatem, L., Bromberg, K., Augenbraun, M., Premsrirut, P., Libien, J., & Norin, A.J. (2021) Administration of high titer convalescent anti-SARS-CoV-2 plasma: association with improved survival of hospitalized Covid-19 patients. [Human Immunology]

Mendoza, R. Saha, N. Momeni, A. Gabutan, E, Alawad, M. Dehghani, A. Diks, J. Lin, B. Wang, D. Alshal, M., Fyke, W., Alshal, M., Wang, B., Himanen, J., Premsrirut, P., & Nikolov, D.B. (2021) Ephrin-A1 and the sheddase ADAM12 are upregulated in COVID-19 [Cell Reports]

Manuscripts in preparation

Fyke, W., Premoli, M., Middei, S., Lemaire-Mayo, V., Wohr, M., Crusio, W.E., Marsicano, G., & Pietropaolo, S. (2021) Communication during post-natal development and adulthood in the CB1 mouse: Implications for Autism Spectrum Disorder. Target journal: Autism Research

Premoli, M*, Fyke W*, Lemaire-Mayo, V., Belloochio, L., Lecorf, K., Wooley-Roberts, M., Crusio, W.E., & Pietropaolo, S. (2020) Evaluation of the neurobehavioral effects of CBDV administration in the Fmr1-KO mouse model of Fragile X Syndrome: the relevance of early treatments. Target journal: Neuropsychopharmacology

Crusio, W. E. Lemaire-Mayo, V. Fyke, W. Premoli, M., Subashi, E., Delprato, A., & Pietropaolo, S. Effects of prenatal stress on the behavior of Fmr1 knock-out mice. Target journal: Behavioral Brain Research

*Co-first author