Partial genetic deletion of Nrg1 interacts with stress during adolescence to alter behaviour, NMDA receptor expression and dendritic morphology in mice: implications for understanding the pathogenesis of schizophrenia

Abstract

Schizophrenia is a heterogeneous mental disorder affecting approximately 1% of the world’s population and the interplay of specific genes and environmental factors at critical early developmental periods is thought to be involved in its pathogenesis. The plastic nature of the adolescent brain makes it particularly sensitive to stress, which is a major environmental factor associated with the disorder. Hypofunctioning of glutamatergic neurotransmission, in the form of dysfunction in N-methyl-D-aspartate receptor (NMDAR) and aberrant retraction of dendrites and loss of dendritic spines has been proposed to account for the cognitive impairments and reductions in grey matter volume in the prefrontal cortex and hippocampus observed in schizophrenia. A leading candidate for genetic susceptibility to schizophrenia is Neuregulin 1 (NRG1), which regulates various developmental processes including synapse formation and plasticity of dendritic morphology. The present thesis examines the effects of adolescent restraint stress on various neurobehavioural parameters in the Nrg1 heterozygous (Nrg1 HET) mouse model of schizophrenia. Here, Nrg1 HET mice exhibited behavioural deficits, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, NMDAR hypofunction and aberrant dendritic morphology (in key corticolimbic regions of the brain) in response to stress during adolescence. This may have relevance to better understanding the pathogenesis of schizophrenia.