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Characteristics of the effects of genetic variation in rodent models of risk for schizophrenia and neurodevelopment disorder

Pass, Rachel Louise 2019. Characteristics of the effects of genetic variation in rodent models of risk for schizophrenia and neurodevelopment disorder. PhD Thesis, Cardiff University.
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Abstract

Various genetic factors increase the risk of developing a psychiatric disease like schizophrenia. This includes large deletions or duplications known as copy number variants (CNVs). Genetic investigations have converged on specific pathways, implicating them in the development of schizophrenia. These key pathways include synaptic functioning, post-synaptic density (PSD), and glutamatergic functioning. The PSD is important for synaptic plasticity, a process thought to represent the molecular basis of learning and memory. As such many of the cognitive impairments observed in schizophrenia are proposed to occur as a result of abnormal synaptic plasticity. CNVs affecting Discs large homolog 2 (DLG2) have been associated with psychiatric disease in human genetic studies. DLG2 is an important part of the PSD involved in the regulation of glutamatergic functioning through interaction with glutamatergic receptors NMDA and AMPA. Previous deficits were observed in a knock out (KO) Dlg2 mouse model in complex cognitive processes involving flexibility. Similar phenotypes were observed in humans carrying DLG2 CNVs. Research into Dlg2 mutation is still limited, especially its behavioural impact. This thesis aimed to characterise two different rodent models (mouse and rat) of Dlg2 heterozygosity. In both models basic molecular characterisation was conducted on the impact of the genetic lesion. In the mouse model, Dlg2tm1a(EUCOMM)Wtsi , a range of basic behavioural tasks were used that had not previously reported in the strain, discovering two specific learning phenotypes: deficient motor learning, and reduced acoustic startle response and habituation. Impaired habituation to a context was also observed during a locomotor activity task. Further investigation was conducted into the motor learning phenotype across multiple days. From this it was determined that the deficit was most apparent during the earliest phase of motor learning. Cellular investigation partially implicated reduced neuronal activity in a brain region important for motor learning, M1, in this phenotype. The impact Dlg2 mutation on adult neurogenesis was also examined, which has previously been proposed as a synaptic risk convergent phenotype. In contrast to previous studies in other risk models no changes were found. Finally, anxiety and motor learning were investigated in the rat. Like the mouse no anxiety phenotypes were found, but in contrast no motor learning impairment was found. Associative learning was probed using a contextual fear conditioning paradigm. No differences were found, including extinction learning, in contrast to the previously reported deficit. A big advantage of the rat over the mouse is the reduced expression of Dlg2 in the hippocampus and PFC, as opposed to just the PFC. This better mimics the dysfunctional network observed in schizophrenia and can be capitalised on to study behaviours reliant on these regions.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 13 September 2019
Last Modified: 13 Sep 2019 13:06
URI: http://orca-mwe.cf.ac.uk/id/eprint/125436

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