An animal model of gene-environment interaction in schizophrenia

Summary

An An animal model of gene-environment interaction in schizophrenia

Supervisor(s)

Dr Jonathon Arnold

Research Location

Camperdown - School of Medical Sciences - Bosch Institute

Program Type

Masters/PHD

Synopsis

Schizophrenia (SCZ) arises due to a complex interaction between genetic and environmental factors during early neurodevelopment, culminating with disease onset in late adolescence/early adulthood. This project aims to model in mice how genetic vulnerability interacts with environmental insults to disturb brain maturation subserving the development of SCZ symptoms. Our unique model focuses on a SCZ susceptibility gene, neuregulin 1 (NRG1), and two environmental insults linked to SCZ, early life stress and adolescent cannabis use. In rodents such insults promote loss of dendritic spines and long-lasting behavioural deficits. This is significant as dendritic spines support excitatory synaptic connections which are less abundant in SCZ brain. The brains of SCZ patients show reduced receptor (NMDAr) levels, a key regulator of dendritic spine growth and maturation. Mice heterozygous for the Nrg1 gene (Nrg1 HET mice) provide a powerful model of SCZ as they have dysfunctional NMDAr and display a time-dependent expression of SCZ-related behaviour. We have data showing repeated adolescent stress exposure in these mice unmasks attention deficits earlier than in the absence of stress. Here we aim to examine whether this is subserved by a genetic vulnerability to stress-induced NMDAr dysfunction and loss of dendritic spines in key cognitive areas of the brain. Further, we will observe whether repeated environmental insults (e.g. prenatal stress and adolescent cannabinoid exposure) amplifies neurobehavioural deficits. Once our model has been developed, we will test whether we can restore NMDAr function and dendritic spine growth. Recombinant Nrg1 (rNrg1) and the atypical antipsychotic clozapine are effective in this regard, therefore they will be the drugs of choice tested in our model.

Additional Information

Techniques:

  • Use of transgenic mice
  • Animal behavioural analysis
  • Immunohistochemistry
  • Autoradiography
  • Quantitative PCR
  • Western blotting
  • Cell line and primary culture of tissue

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Keywords

Schizophrenia, Cancer, Psychosis, Addiction, Drug abuse, Pharmacology, Neuroscience, Cannabinoids, Transgenic mice models, Multidrug resistance, ABC transporters, Therapeutics & adverse drug effects, Behavioural & psychiatric disorders, Genes in biology & medicine, Neuroscience & psychology, Pharmacology & therapeutics

Opportunity ID

The opportunity ID for this research opportunity is: 1

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