Lentiviral-mediated gene delivery to investigate the functional role of neuropsychiatric genes

Genetic studies have led to the identification of several candidate genes, some novel and others established, that may contribute to the risk of developing neuropsychiatric disorders. For example, dopamine receptor genes are established candidates for a number of psychiatric disorders such as Parkinson’s Disease, alcohol addiction and mood disorders. On the other hand, a gene of unknown function, AUTS2 (Autism susceptibility candidate 2), has recently been associated with alcohol consumption in a GWAS meta-analysis performed by our group. Interestingly, it has been associated with a broad range of neuropsychiatric disorders including autism, epilepsy and schizo-affective disorders. This thesis looked to address two broad aims: to establish lentiviral-mediated gene delivery technique in vivo by delineating the role of two well characterised Dopamine receptors D2R and D3R and to functionally characterise the role of AUTS2. By successfully establishing lentiviral mediated gene manipulation in vitro and in vivo, this thesis presents data for a similar role of nucleus accumbens D2R and D3R in novelty-induced locomotion while these receptors have a differential function in the regulation of light-induced locomotor behaviour in rats. Additionally, using molecular biology and in silica methods, this thesis demonstrates that AUTS2 is a nuclear protein and presents indications of its function as a neurodevelopmental gene with a potential role in neural migration, although its specific role has yet to be corroborated. Collectively, findings from this thesis will increase our understanding of the genetic link with brain function and behavioural traits. This will therefore have implications for overall neuropsychiatric research, as it will help understand molecular mechanisms underlying these conditions and possibly direct in the identification of potential therapeutic targets.

Name dc:type.qualificationname

Doctor of Philosophy

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

King's College London

Year dc:date.issued

2013

Author dc:creator

• Fernandes, Alinda

Advisors dc:contributor.advisor

• Schumann, Gunter
• Desrivieres, Sylvane

Language dc:language

eng

Identifier

oai:kclpure.kcl.ac.uk:studenttheses/b6392e47-e94b-4e64-b343-e7eafd696b26

OAI identifier oai:identifier

oai:kclpure.kcl.ac.uk:studenttheses/b6392e47-e94b-4e64-b343-e7eafd696b26