The role of neuroligin 3 in cognitive function

© 2018 Dr Rebecca H C NorrisNeuroligins (NLGNs) are members of trans-synaptic protein complexes that mediate synaptic transmission and plasticity, both of which are critical for information processing and cognition. Genetic risk factors for a range of neurodevelopmental disorders disproportionately converge upon synaptic genes, including NLGNs. Although mutations in NLGN3 are linked to ASD, a condition with characteristic cognitive impairments, little is known about the impact of a loss of function of NLGN3 on cognitive processing. This thesis describes the impact of a loss of function of Nlgn3 on a range of distinct cognitive functions in mice, using rodent touchscreen technology. In Chapter 2, we assessed Nlgn3 KO mice on a battery of cognitive tests to explore the involvement of Nlgn3 in operant learning, associative learning, behavioural flexibility, response inhibition and motivation. We found that loss of function of Nlgn3 did not impact operant learning, discrimination learning, extinction learning or appetitive motivation, but had striking impacts on behavioural flexibility indexed by perseverative incorrect responding as well as performance on a reversal learning task. In Chapter 3 we extended the characterisation of Nlgn3 KO mice to probe working memory, pattern separation, signal detection and sustained attention. We found that Nlgn3 KO mice displayed normal pattern separation and a subtle but significant impairment in working memory, suggestive of a shift in the balance between stability and flexibility. Loss of Nlgn3 additionally resulted in robust improvements in measures of sustained attention and signal detection, implicating Nlgn3 in processes underlying allocation of attention. However, performance of Nlgn3 KO mice was also more severely impacted by increasing demands on perceptual or attentional processing, suggesting a reduced ability to scale up the allocation of processing resources under challenging conditions. In Chapter 4 we examined relational memory and flexibility by adapting a novel version of the touchscreen transitive inference task. After validating that WT mice were able to perform our adapted version of the touchscreen transitive inference test, we assessed both Nlgn3 KO and Nlgn3 R451C mice to compare two different models of Nlgn3 dysfunction on relational memory. We show that both Nlgn3 KO and Nlgn3 R451C mice display intact relational memory. However, both Nlgn3 mutant mice exhibited elevated behavioural flexibility, consistent with our results from Chapter 2. Across all chapters, our results indicate Nlgn3 KO mice exhibit longer response times than WT mice across tests that require discrimination of complex stimuli, strongly implicating Nlgn3 in processes underlying perceptual processing. Collectively, the findings from this thesis show that Nlgn3 is involved in aspects of behavioural flexibility, attention and perceptual processing. These studies contribute to our understanding of the function of Nlgn3, and more broadly the impact of synaptic gene dysfunction in aspects of cognition relevant to neurodevelopmental disorders