Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders characterized by social communication impairments and restricted interests. Epilepsy is a brain disorder diagnosed after the occurrence of at least one epileptic seizure. ASD and epilepsy are often comorbid. The integrin αVβ3 is a synaptic cell adhesion molecule that binds to counter-receptors and extracellular matrix proteins. Itgb3, the gene encoding the β3 subunit of integrin αVβ3, has been associated to ASD in humans, and constitutive knockout (KO) mice for this gene exhibit ASD-like behaviors, while brain-specific conditional KO mice for the other subunit of integrin αVβ3 (αV) have higher propensity for seizures. Integrin αVβ3 may, therefore, play important neuronal roles in brain regions relevant for ASD and epilepsy. To test this hypothesis, I expanded the behavioral characterization of Itgb3 constitutive KO mice and characterized the behavioral phenotype of an Itgav conditional KO mouse specific for excitatory neurons of the forebrain. In these mouse models, I also investigated the synaptic dysfunctions of excitatory synapses onto layer V pyramidal neurons of the medial prefrontal cortex. I find that loss of integrin αVβ3 leads to deficits in social novelty preference, hyper-reactivity to acoustic stimuli of high intensity, and reduces the threshold for pharmacologically induced seizures. This correlates with a reduction in the content of GluA2-lacking AMPA receptors in excitatory inputs to layer V pyramidal neurons.
|Titolo della tesi:||Role of αVβ3 integrin in cortical synaptic transmission: relevance for Autism Spectrum Disorder and Epilepsy|
|Data di discussione:||21-feb-2019|
|Appare nelle tipologie:||Tesi di dottorato|