Shared engagement deficit phenotype and circuit-mechanism in four mouse models of Autism Spectrum Disorders

Zaina, Gloria. Shared engagement deficit phenotype and circuit-mechanism in four mouse models of Autism Spectrum Disorders. 2023, Doctoral Thesis, University of Basel, Associated Institution, Faculty of Science.

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Official URL: https://edoc.unibas.ch/96108/

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Autism Spectrum Disorder (ASD) is among the most demanding conditions worldwide, in terms of disability burden for the individuals and their families, as well as economic burden for the occupational systems. At the moment there is no effective treatment for the ASD core symptoms. There are some treatments and behavioral interventions that are used to alleviate comorbidities, in order to reduce difficulties in the daily life, but it still remains a life-long condition, whose mechanistic basis is not completely understood.
In this dissertation, we aimed at investigating the contribution of circuit-level dysfunctions to the behavioral phenotype of four monogenic mouse models, with high-penetrant ASD-linked mutations at the level of the genes: Shank3, Fmr1, Cntnap2 and Nrlg3. Firstly, we carefully assessed the behavioral phenotype of these mice, evaluating it in parallel with the behavioral phenotype characterized in the lab. previously in the Shank3 model. This allowed us to identify a common failure-to-engage phenotype present upon novel context re-exposure across all these mice with ASD-predisposing mutations, but not in WT mice.
Then, we asked whether a convergent neural circuit mechanism underlying this common phenotype could be identified in these ASD mouse models. We approached this question by investigating the involvement of two groups of cortico-striatal projection neurons to the Tail of Striatum (TS): one, originating from Prelimbic cortex (PL->TS), previously involved in Shank3 model, and the second one, originating from Perirhinal cortex (PRC->TS), not previously involved in any of these mutants. Parallelly, we also studied the contributions of dopamine modulation at the level of the D1-MSNs and D2-MSNs plasticity in TS. Finally, to corroborate our functional evidences, we performed two neuronal tracing studies, aiming at identifying the target regions within TS of the two cortico-striatal projections investigated.
Collectively, through a series of gain and loss of function chemo-genetic experiments, combined with pharmacological DA antagonism experiments and tracing studies, we revealed the existence of two distinct cortico-striatal neuronal-circuit mechanisms, one causally responsible for the long-term induction of the shared failure-to-engage phenotype of the ASD mutants, and the other one involved in its context-specific memory consolidation across subsequent re-exposures.
Advisors:Arber, Silvia
Committee Members:Caroni, Pico and Bagni, Claudia
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Neurobiology > Cell Biology (Arber)
09 Associated Institutions > Friedrich Miescher Institut FMI > Neurobiology > Plasticity of neuronal connections (Caroni)
UniBasel Contributors:Arber, Silvia
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:15253
Thesis status:Complete
Number of Pages:164
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss152536
edoc DOI:
Last Modified:09 Feb 2024 05:30
Deposited On:08 Feb 2024 13:12

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