Tesi di laurea magistrale
Investigating sensorial deficit in Shank3 mutant mice
Corso di studi
BIOLOGIA APPLICATA ALLA BIOMEDICINA
relatore Dott. Ratto, Gian Michele
- Phelan-McDermid syndrome
- Local field potential
- Visual cortex
- Autism spectrum disorder
Data inizio appello
Data di rilascio
The Phelan-McDermid syndrome (PMD) is a genetic disorder caused by deletion or rearrangements of the long arm of the chromosome 22, and it is classified as Autism Spectrum Disorder (ASD).<br>One of the genes most often deleted is Shank3 a key actor in the assembly of the Post-Synaptic Density (PSD); In particular, its interaction with Homer, influences the functions of the metabotropic glutammate receptors (mGluR5)<br>In our experiments we are interested to determine:<br>1) if the loss of Shank3 might bring sensorial deficits, especially in the visual cortex;<br>2) how the excitability of the neurons change in the absence of Shank3 and how it can explain the high co-morbidity of ASD and epilepsy, present in PMD as well.<br>To evaluate those hypothesis we used extracellular field potential recordings in vivo in the primary visual cortex in KO mice for the exon 11 of Shank3.<br>We measured the visual potential evoked by alternating checkerboards with differential contrasts and built a contrast sensitivity curve , that resulted different in KO and wild-type controls, revealing hyper-excitability and a loss of the gain control.<br>To explain the increase in excitability in a disease affecting the excitatory synapse we theorized that the loss of Shank3 causes a worse phenotype on the glutamatergic synapses on the inhibitory interneurons, determining a deficit in the recruit of the inhibitory feedback.<br>To test this hypothesis, we tried pharmacological treatments that increase the efficacy of the inhibitor transmission like midazolam, a molecule that enhances the sensibility of GABA-A receptors, rescuing their contrast sensitivity. Our study proved a clear link between the absence of Shank3 and a deficit in the neural circuitry, and suggested novel therapeutic targets.
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