Show simple item record

dc.contributor.advisorKind, Peteren
dc.contributor.advisorWyllie, Daviden
dc.contributor.authorToft, Anna Karina Huggeren
dc.date.accessioned2019-12-12T15:31:30Z
dc.date.available2019-12-12T15:31:30Z
dc.date.issued2019-11-25
dc.identifier.urihttps://hdl.handle.net/1842/36625
dc.description.abstractIntellectual disability (ID) and autism spectrum disorder (ASD) are two of the most common developmental disorders affecting 3–5% of the population. These disorders have a high burden on society with no efficient treatment options. This is complicated further by the high comorbidity between ID and ASD, as well as epilepsy. Understanding the aetiology and pathophysiology of ID and ASD is of vital importance in order to find better treatment options for the patients and their families. Recent genomic studies have identified hundreds of genetic variants contributing to the incidence of ID and ASD. Many of these genes are important for synaptogenesis and maintenance of synaptic function, such as the neuroligins (NLGN1-4), neurexin 1 (NRXN1), fragile x mental retardation 1 (FMR1), Synaptic Ras GTPase-activating protein 1 (SYNGAP1), and SH3 And Multiple Ankyrin Repeat Domains 3 (SHANK3). Understanding how the proteins of these genes operate, and how they influence synaptic development and function will increase our understanding of what goes wrong in their absence. In this thesis, the role of two synaptic proteins across development were examined in principal cells of the amygdala: NLGN3 and SynGAP. Neuroligins are postsynaptic cell adhesion molecules that bind to presynaptic neurexins, and are required for both excitatory and inhibitory synapse maturation and function. The Nlgn3-/y rat model was utilised to study the role of the NLGN3 isoform in this study. SynGAP is one of the major constituents of the postsynaptic density (PSD). However, there are contrasting hypotheses as to how SynGAP mediates its effects on synaptic morphology and function. One hypothesis suggests that SynGAP plays a key role in regulating the structural composition of the PSD by sequestering PSD-95, and thereby modulating synaptic function. The alternative hypothesis suggests that SynGAP regulates synaptic structure/function through its GTPase activating activity of Ras/Rap and their downstream signalling pathways. To test the relative roles of SynGAPs scaffolding and signaling functions in disease pathophysiology, two genetically modified Syngap rat models were used; one with a heterozygous deletion of the GAP-domain (Syngap+/∆GAP); and one with a null-mutation (Syngap+/-). It was found that Nlgn3-/y displayed an age-dependent increase in intrinsic excitability compared to WT littermates, as well as an age-dependent increase in miniature inhibitory postsynaptic currents (mIPSCs) amplitude. No change was observed on excitatory postsynaptic currents in Nlgn3-/y. Furthermore, a deficit in long term potentiation (LTP) at thalamic inputs to the lateral amygdala (LA) was found using a 30Hz induction protocol. No difference was found in intrinsic properties in either of the two SynGAP models at two weeks of age, but at four weeks divergence were found between the two. In the LA, Syngap+/- displayed an increase in excitability, whereas Syngap+/∆GAP was comparable to WT. Conversely in the basal amygdala (BA), Syngap+/- did not present with any changes in intrinsic properties, in opposition to Syngap+/∆GAP, which exhibited a decreased firing rate compared to WT. Both models had a deficit in LTP from thalamic input into the LA, but only Syngap+/- demonstrated a decrease in paired-pulse facilitation. Taken together, this work shows that NLGN3 is important for development of normal cellular and synaptic functions. Furthermore, this work helps to highlight the different roles exerted by the functional domains of SynGAP.en
dc.language.isoen
dc.publisherThe University of Edinburghen
dc.subjectsynapsesen
dc.subjectintellectual disabilitiesen
dc.subjectAutism Spectrum Disordersen
dc.subjectamygdalaen
dc.subjectsynaptogenesisen
dc.subjectNLGN1-4en
dc.subjectfragile x mental retardation 1en
dc.subjectFMR1en
dc.subjectSYNGAP1en
dc.subjectSHANK3en
dc.subjectNLGN3en
dc.titleImpact of two autism related genes on amygdala physiologyen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


Files in this item

This item appears in the following Collection(s)

Show simple item record