Neonatal ibotenic acid lesions of the ventralhippocampus : the effects of stress on gene expression and apoptosis
Ashe, Paula Carmella
Recently, it has been suggested that neurodevelopmental abnormalities underlie schizophrenia. However, it has also been suggested that schizophrenia is a neurodegenerative disease as evidenced by a progressive worsening of symptoms over time. Neurodevelopmental abnormalities may, therefore, create a functionally compromised system that is more susceptible to neuronal atrophy and/or death caused by environmental factors such as stress (a known precipitant of acute psychotic episodes and exacerbant of schizophrenia). This hypothesis was tested using the putative neurodevelopmental model of schizophrenia described by Lipska 'et al'. (1993). The effects of neonatal hippocampal lesions on BDNF mRNA and NMDAR1 mRNA, factors involved in development, cell survival and cell communication, were investigated in adult rats following exposure to a physiological stressor. Apoptosis levels were also investigated in these rats to determine if neurodegeneration was present. Results demonstrate that BDNF mRNA was reduced in the prefrontal cortex and hippocampus of lesioned as compared to sham rats. Increased BNDF mRNA resulted from swim stress in both groups, but the increase in lesioned animals was more pronounced than controls. NMDAR1 mRNA was also reduced in the prefrontal cortex and CA3 and CA1 regions of the hippocampus in lesioned versus sham rats. There was an increase, however, in the dentate gyrus of lesioned versus sham rats. Swim stress increased NMDAR1 mRNA in the prefrontal cortex and decreased it in the hippocampus. There was also an increase in apoptosis in lesioned versus sham rats, with no significant increase in response to stress. Reductions in BDNF mRNA in lesioned versus control animals support the hypothesis that neurodevelopmental lesions may result in a system more susceptible to stressors. Reductions in NMDAR1 mRNA are in accordance with the NMDA glutamate receptor hypofunction theory of schizophrenia. It is possible that reductions in glutamate function can remove the inhibitory effect of GABA, thereby resulting in overexcitation of the system and a potential for neurodegeneration. Increased apoptosis supports the presence of neurodegeneration as an ongoing phenomenon. Even though the effect of acute stress on apoptosis was not significant, the very small increases demonstrated can have significant functional consequences over extended periods of time.
DegreeDoctor of Philosophy (Ph.D.)
SupervisorJuorio, Augusto V.
Copyright DateJuly 2000