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Tesi etd-09082016-164952


Tipo di tesi
Tesi di laurea magistrale
Autore
ALBANESI, MARCO
URN
etd-09082016-164952
Titolo
Investigating sensorial deficit in Shank3 mutant mice
Struttura
BIOLOGIA
Corso di studi
BIOLOGIA APPLICATA ALLA BIOMEDICINA
Commissione
relatore Dott. Ratto, Gian Michele
Parole chiave
  • Phelan-McDermid syndrome
  • Local field potential
  • Visual cortex
  • Autism spectrum disorder
Data inizio appello
26/09/2016;
Disponibilità
parziale
Riassunto analitico
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).
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)
In our experiments we are interested to determine:
1) if the loss of Shank3 might bring sensorial deficits, especially in the visual cortex;
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.
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.
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.
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.
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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