Development and behavioural validation of a neurodevelopmental model for schizophrenia

  • Victoria Fasolino

Student thesis: Master of Philosophy


Schizophrenia is generally characterised by three major symptom domains, namely positive, negative and cognitive symptoms. Antipsychotics have been the cornerstone of treatment for over 60 years. Despite the optimism that accompanied the arrival of the newer atypical antipsychotics, it is evident that these drugs are not alleviating a number of symptoms associated with the disorder. In particular, a major clinical unmet need in the management of schizophrenia is the treatment of negative and cognitive symptoms. Improved understanding of the pathophysiology of these deficits depends on the availability of properly validated animal models. There is accumulating evidence for the role of inflammatory processes in the aetiology of neuropsychiatric disorders. More specifically, epidemiological studies have shown an association between maternal infection and subsequent risk of schizophrenia in the offspring (Brown, 2012). Thus, maternal immune activation (mIA) is emerging as a key model for schizophrenia in animals (Meyer and Feldon, 2012). The aim of this project is to set up a maternal immune activation model of schizophrenia symptomatology in rats. This will be achieved by following pathological changes in mother and offspring, including detailed characterisation of behavioural development in offspring at different time points. Poly(I:C) administration at 10 mg/kg (i.p.) induced a robust immune response in pregnant Wistar rats. It significantly increased maternal plasma IL-6 levels 3 hours post injection, but did not affect maternal body weight or core body temperature at 3, 6 or 24 hours post injection. Poly(I:C)-induced mIA did not affect litter size or communicative behaviour in early postnatal life. Behavioural deficits were emerging during adolescence, with a trend for increased anxiety-like behaviour and a potential cognitive impairment observed in adolescent males. By adulthood, social behaviour deficits were emerging (but not significant) in female rats that displayed a significant cognitive deficit in the novel object recognition test. This behavioural phenotype may be of relevance to symptoms observed in schizophrenia. Subtle deficits in early behaviour and neurobiology may indicate future abnormal behaviour, and as such this stage is critical for testing preventative strategies. Ultimately, this model will be used to identify early neurodevelopmental changes in offspring with the aim of modifying the abnormal trajectory.
Date of Award1 Aug 2018
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorBill Deakin (Supervisor), Alison Yung (Supervisor), Joanna Neill (Supervisor) & Michael Harte (Supervisor)

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