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Identification of non-coding RNAs associated with autism spectrum disorder and cognitive assessment of NMDA receptor modulators in mouse

Koç, Baran. Identification of non-coding RNAs associated with autism spectrum disorder and cognitive assessment of NMDA receptor modulators in mouse. 2019, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_13432

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Abstract

Autism spectrum disorder (ASD) is a common neurodevelopmental condition characterized by impaired social interaction and communication as well as restricted and repetitive behaviors. The ASD etiology is complex and ill-understood. A combination of genetic and environmental factors is thought to be implicated in the ASD pathology. Many mutations have been linked to ASD in protein-coding genes. But long non-coding RNAs (lncRNAs) have attracted particular attention due to their role in the regulation of gene expression. In this thesis, I aimed to understand the transcriptional regulation of sense and antisense RNA transcripts related to ASD (Chapter 1), and to reveal the brain region-specific roles of GluN2B and Syngap1 in cognition (Chapter 2).
In Chapter 1, the primary focus was on 100 genes that were associated with ASD. Their sense and antisense transcript expression was profiled using a deep RNA sequencing approach. A small fraction of the examined transcripts showed brain region-specific enrichment in the medial prefrontal cortex (mPFC) or striatum across mouse development. Using this data, a de novo antisense transcriptome was generated with mPFC- and striatum-specific annotations, which yielded more than 70,000 antisense transcripts. A subset of these transcripts was validated in the mouse brain by qPCR. Moreover, the blast analysis revealed that a fraction of the de novo transcripts had high complementary coverage with the human genome.
In Chapter 2, the effects of NMDA receptor (NMDAR) antagonism on cognition were investigated. First, a touchscreen-based spatial working memory task for pharmacological testing was successfully optimized. Using this task, it was then demonstrated that the systemic administration of non-subunit selective uncompetitive antagonist MK-801 and GluN2B-selective antagonist impaired working memory performance in mice by affecting different behavioral measures. Furthermore, by combining systemic NMDAR antagonism with genetic suppression of GluN2B or Syngap1 in mPFC, it was observed that loss of GluN2B exacerbated the MK-801-induced working memory impairment while Syngap1 knockdown animals showed reduced impairment.
Overall, the methods and results demonstrated in this thesis contribute to the understanding of the interplay of sense-antisense partners in the regulation of ASD-related genes and provide insight into how NMDARs and an associated cellular signaling molecule contribute to specific features of working memory. The results presented here could be used to define mechanistic targets in preclinical animal models with the ultimate goal of developing novel therapeutics for people in need.
Advisors:Zavolan, Mihaela and Hall, Benjamin J. and Barkat, Tania Rinaldi
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Computational & Systems Biology > Bioinformatics (Zavolan)
UniBasel Contributors:Zavolan, Mihaela
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:13432
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (vi, 105 Seiten)
Language:English
Identification Number:
Last Modified:13 Dec 2019 05:30
Deposited On:12 Dec 2019 09:26

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