Pizzella, Amelia (2024) Altered synaptic plasticity in neurodevelopmental and neurodegenerative diseases. [Tesi di dottorato]

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Abstract

Synaptic plasticity refers to activity-dependent adjustments of neuronal circuits which enable remodeling of preexisting synaptic connections to change strength or efficiency of synaptic transmission and thereby modulate neuronal excitability. The growing evidence showing the ability of nerve endings to synthesize proteins independently from the cell body provides a new perspective for synaptic plasticity. Indeed, synapses can respond to the local stimuli by changing quickly and appropriately their proteins pattern. Moreover, recent studies suggested that synaptic plasticity may also be mediated by the release of extracellular vesicles from synaptic terminals. In addition to regulating the extracellular neuronal environment, these extracellular vesicles mediate long distance cell-cell communication. Interestingly, altered mechanisms of synaptic plasticity has been demonstrated in various neurodegenerative and neurodevelopmental (NDDs) pathologies, associated with synaptic dysfunctions and therefore referred to as synaptopathies. This thesis aims to unveil potential common mechanisms underlying these neuropathologies, and to identify novel therapeutic target. As an in vitro model of nerve endings detached from neuronal soma, synaptosomal fraction was isolated from the cerebral cortex of two different animal models for NDDs, i.e. BTBR mouse for Autism Spectrum disorder (ASD), and Ube3Atm1Alb/J mouse for Angelman syndrome (AS). The results of biochemical and morphological analyses indicated that the synaptic system of protein synthesis was deregulated in both NDDs. This investigation was extended to a neurodegenerative disease that displays neuronal impairments already during neurodevelopment, the Myoclonic Epilepsy type 1 (EPM1). In particular, synaptosomal fraction was isolated from human cerebral organoids (hCOs) generated from induced pluripotent stem cells (iPSCs) of EPM1 patients. In this human model of synaptic regions, it was demonstrated a deficit of the synaptic system of protein synthesis, but also an alteration of extracellular vesicles release from nerve endings. A potential candidate for the treatment of synaptopathies is the receptor 7 of serotonin (5-HT7R), which is tightly involved in neuroplasticity. Indeed, in this study we demonstrated that stimulation of 5-HT7R with a selective agonist was able to reverse the synaptic deficits in ASD and AS. Altogether, this work indicates the alterations of synaptic plasticity mechanisms as a common deficit in neurodevelopmental and neurodegenerative diseases for which targeting 5-HT7R could be an appropriate candidate for therapeutic strategy.

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