Neuregulin 1-Erbb4 in the rodent prefrontal cortex: Investigations of schizophrenia-related behaviours and signalling pathways.
PhD thesis, University of Glasgow.
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Schizophrenia is a severe, chronic and debilitating psychiatric disorder. Current therapies have no efficacy in treating the cognitive impairments which are largely responsible for the poor quality of life of schizophrenia patients and contribute to the massive economic burden that is associated with the disorder.
Although it is known that schizophrenia is highly heritable, the underlying genetic basis is still poorly understood due to the complex polygenetic nature of the disorder. Several candidate genes which are thought to increase risk for the incidence of schizophrenia have been identified. Two such schizophrenia candidate genes are neuregulin 1 (NRG1) and v-erb-a erythroblastic leukaemia viral oncogene homolog 4 (ERBB4). As well as the genetic evidence from genetic association studies, studies of animal models and the endogenous biological functions of NRG1 and ERBB4 in the CNS suggest that these genes may play an important role in the pathophysiology of schizophrenia. However, very little is known about the functions of these genes in specific brain regions in adulthood with respect to cognition.
To address this, I have utilised recombinant adeno-associated viral particles (rAAVs) as a vehicle to mediate knockdown of the expression of Erbb4 specifically within the medial prefrontal (mPFC) cortex of adult rats. This allows for a spatially and temporally controlled investigation of the role that Erbb4 signalling may play in prefrontal cortex-dependent behaviours in adulthood.
Following initial in vitro and in vivo validation of the functionality of the rAAVs, further in vivo studies confirmed that, five weeks after stereotaxic injection of rAAVs encoding a short hairpin sequence corresponding to Erbb4 (shErbb4.rAAV), into the mPFC of rats, there was significant Erbb4 protein knockdown, as analysed by ELISA. Subsequent western blot analysis revealed that Erbb4 knockdown consequently increased the level of Nrg1 expression and decreased the activity of Akt signalling, but had no effect on Erk signalling.
Erbb4 knockdown specifically within the mPFC increased performance accuracy in the 5-choice serial reaction time task at 5 weeks post-surgery. Furthermore, viral mediated Erbb4 knockdown specifically within the mPFC heightened the
sensitivity to the locomotor inducing effects of amphetamine. There were, however, no effects of Erbb4 knockdown on pre-pulse inhibition at any time points assessed. These results indicate that Nrg1-Erbb4 signalling in the PFC modulates cognitive performance but not sensorimotor gating, and that dopaminergic transmission may be regulated by Nrg1-Erbb4 signalling.
In conclusion, this study highlights the ability of viral mediated gene manipulation to investigate regionally specific roles of schizophrenia candidate genes in adulthood in terms of cognition and downstream signalling pathways. This may translate to a better understanding of how these genes may exert potentially pathophysiological effects in patients and ultimately lead to improved treatments.
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