Autism spectrum disorders (ASDs) represent a heterogeneous group of neurodevelopmental disorders characterised by deficits in social interaction and communication, and by restricted and stereotyped behaviour. The diagnosis of autism is based on behavioural observation of the subject as research has not yet identified specific markers. Today, several studies show that disturbances in sensory processing are a crucial feature of autism. Indeed, around 90% of individuals diagnosed with autism show atypical responses to various sensory stimuli. These sensory abnormalities (described as hyper- or hypo-reactivity to sensory stimulation) are currently recognised as diagnostic criteria for autism. Among the sensory defects, tactile abnormalities represent a very common finding impacting the life of autistic individuals. It has been shown how abnormal responses to tactile stimuli not only correlate with the diagnosis of autism but also predict its severity. Indeed hypo-responsiveness to tactile stimuli is associated with greater severity of the main symptoms of autism. To date, the neural substrates of these behaviours are still poorly understood. Over the years, the use of genetically modified animal models has enabled a major step forward in the study of the aetiology of autism spectrum disorders. Interestingly, several animal models that carry autism-related mutations also show deficits of a sensory nature. This is the case with the Shank3b-/- and Cntnap2-/- mouse models, strains in which the expression of the gene in question is suppressed. The SHANK3 gene encodes for a crucial protein in the structure of the postsynaptic density of glutamatergic synapses. In humans, haploinsufficiency of SHANK3 causes the Phelan-McDermid syndrome, a neurodevelopmental disorder characterised by ASD-like behaviour, developmental delay, intellectual disability and absent or severely delayed speech. Individuals with Phelan-McDermid syndrome often show dysfunctions in somatosensory processing, including disturbances in tactile sensitivity. CNTNAP2 codes for CASPR2, a transmembrane protein of the neurexin superfamily involved in neuron-glia interactions and clustering of potassium channels in myelinated axons. Missense mutation in CNTNAP2 is causative of cortical dysplasia-focal epilepsy syndrome (CDFE), a rare disorder characterized by epileptic seizures, language regression, intellectual disability, and autism. Following these findings, mice lacking the Shank3b isoform (Shank3b-/-) and Cntnap2 gene (Cntnap2-/-) show autistic-like behaviours.
In this study, we used an interdisciplinary approach (behavioural, molecular, and imaging techniques) to study the neuronal substrates of whisker-mediated behaviours in genetic mouse models of ASD. We performed two behavioural tests, namely the textured novel object recognition test (tNORT) and the whisker nuisance test (WN) to have in-depth insight in whisker dependent behaviours. Following behavioural assessment, through a molecular approach, we investigated the neural underpinnings of this aberrant behaviour. We evaluated neuronal activation in key brain areas involved in the processing of sensory stimuli via c-fos mRNA in situ hybridization. Finally, using a seed-based approach in resting-state functional magnetic resonance imaging (rsfMRI) we probed the functional connectivity phenotype of these mutant mice. The contribution of the peripheral nervous system to sensory processing was also assessed via RT-qPCR at the level of the trigeminal ganglion. Sensory abnormalities that characterize ASDs represent a symptom of primary relevance in the life of autistic individuals. Scientific research has only recently addressed this important aspect and animal models represent a useful preclinical tool to investigate the causal role of genetic mutations in the aetiology of ASDs. In such context, the complementary approach used in this work represents a crucial step to the understanding of sensory-related deficits which characterize ASD.
| Identifer | oai:union.ndltd.org:unitn.it/oai:iris.unitn.it:11572/370647 |
| Date | 27 February 2023 |
| Creators | Balasco, Luigi |
| Contributors | Balasco, Luigi, Bozzi, Yuri |
| Publisher | Università degli studi di Trento, place:TRENTO |
| Source Sets | Università di Trento |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/doctoralThesis |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | firstpage:1, lastpage:118, numberofpages:118 |
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