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Synaptic functions of integrin-mediated cell adhesion in physiological conditions and autism-related abnormalities in mice

Final Report Summary - SYNAMPADHESION (Synaptic functions of integrin-mediated cell adhesion in physiological conditions and autism-related abnormalities in mice)

Brain function critically depends on how neurons communicate with each others at specialized contact sites, the synapses. Cell adhesion molecules (CAMs) are key synaptic proteins that provide the molecular framework for organizing structural and functional aspects of synaptic connections. However, little is known about the underlying molecular mechanisms. We do not know how CAMs dynamically regulate synaptic strength in response to synaptic interactions and how alterations in the function of some CAMs lead to neurodevelopmental disorders.

The goal of this project is to provide mechanistic insights on how integrins, a major class of synaptic CAMs, regulate synaptic strength in health and disease. To this end, we set out three major objectives: (i) functional significance of the interaction between integrins and AMPA-type glutamate receptors, (ii) functional significance of integrin-mediated cell adhesion for synaptic transmission, (iii) functional significance of synaptic integrins for autism-related phenotypes.

We have focused on characterizing mice knockout for the integrin beta3, which are an animal model for autism spectrum disorders (ASDs). Specifically, we have investigated the brain function of these mice at the morphological and physiological level. Moreover, we have carried out a behavioral characterization of these mice to better elucidate their cognitive and social impairments.

The experiments performed indicate that ablation of integrin beta3 affects the functional properties of synaptic connections between neurons without major morphological alterations. Accordingly, cognitive impairments are detected in these mice.

ASDs are common neurodevelopmental disorders (affecting nearly 1/88 children). They severely impair the emergence of social behaviors and communication, and are incurable. This is most likely because of their complex genetics, which involves hundreds of genes. According to an emerging view, many of the genes implicated in ASDs converge on a limited number of signaling pathways; alterations of these core signaling pathways would ultimately produce the typical symptoms found in autistic individuals. For example, many of the mutations that contribute to ASDs relate to synaptic CAMs. A better understanding of how synaptic CAMs regulate synaptic connectivity and brain function is therefore important for developing effective drug treatments targeting the core symptoms of ASDs. With the aim of unveiling the general principles governing synaptic connectivity under physiological conditions and in autism-related abnormalities, the present research proposal seeks to contribute to this endeavor.

Lorenzo Cingolani is principal investigator at the newly established Center for Synaptic Neuroscience (NSYN), Italian Institute of Technology (IIT), Genoa. His five-year long position has been renewed in February 2017, and he has obtained the Italian habilitation in Physiology as Associate professor.