Sex hormones and schizophrenia: from animal behavioural models to gene targets

© 2017 Dr. Jeehae Jenny SunSex differences in schizophrenia are widely supported with a rich literature, and epidemiological studies have demonstrated a sharp rise in incidence rates for schizophrenia around the onset of puberty and adolescence, which is a time that is hallmarked by fundamental sex hormone-dependent changes. Such observations gave rise to the estrogen hypothesis, which postulates that estradiol exerts a protective role in schizophrenia pathophysiology. However, what has been acknowledged less is that studies describing sex differences in schizophrenia actually suggest a role for estradiol and progesterone, both of which are present predominantly in females. Although it is widely accepted that estradiol and progesterone can interact with key neurotransmitter systems at the behavioural, cellular and molecular levels, the exact mechanisms by which these sex hormones are implicated in schizophrenia still remains unclear. Thus, the overarching aim of this thesis was to further our understanding on the roles of these sex hormones in schizophrenia pathophysiology. To investigate this, animal models of spatial memory and drug-induced psychosis-like behaviours were used during adolescence and adulthood, and investigated ovarian hormone-regulated cortical gene expression changes in rats and their relevance to schizophrenia by utilising human post-mortem schizophrenia brains. This thesis demonstrated several key findings on the effects of ovarian hormones during adulthood and adolescence that have not been previously observed. Firstly, there was a unique effect of hormone deprivation by ovariectomy (OVX) in adulthood to reverse deficits in prepulse inhibition (PPI) induced by apomorphine (a dopamine D1/D2 receptor agonist) in adult mice, an effect that was not observed when mice were OVX during adolescence. In adult mice, findings also showed a U-shaped dose-response curve of estradiol treatment to modulate apomorphine-induced PPI disruption, an effect that was absent during adolescence. estradiol treatment also uniquely lowered baseline locomotion and showed a trend to lower locomotor hyperactivity induced by N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, when administered during adolescence. Importantly, there were interactions between estradiol and progesterone in adult mice that were unique from their individual effects, and the functional outcomes depended on the behavioural paradigm used and the neurotransmitter system targeted. While separate hormone treatments showed a general reinstatement of apomorphine-induced PPI disruption, combining the two hormones together resulted in a response comparable to untreated OVX mice. The combined hormone treatment in adult mice also reduced MK-801-induced locomotor hyperactivity. Neither of these combined hormone treatment effects were observed when administered during adolescence. Further, consistent with previous studies reported in the literature, this thesis demonstrated estradiol's ability to enhance short-term spatial memory performance in adult female mice; however, neither progesterone or the combined estradiol/progesterone treatment had any effect on short-term spatial memory. Overall, these findings support the notion that ovarian hormones during adolescence may influence the trajectory of behaviour into adulthood, albeit under certain experimental conditions. Investigation of cortical gene expression changes after OVX and estradiol treatment revealed several key ovarian hormone- and estradiol-regulated canonical pathways and cellular/molecular functions that have been suggested to be associated with schizophrenia pathophysiology. Such pathways and mechanisms included antioxidant defence, response to oxidative stress, immunological processes such as antigen presentation and complement activation, and the degradation of catecholamine neurotransmitters. Encouragingly, analysis revealed that all genes that were commonly altered by exogenous estradiol treatment in adult OVX rats and in the prefrontal cortex of schizophrenia subjects were associated with annotations of neurological disease, such as schizophrenia, cognitive impairment, and major depression. Finally, the last experimental chapter demonstrated that one of the genes that was significantly altered by OVX in rats, RAPGEF1, was also significantly altered in cortical tissue from schizophrenia subjects, thus further highlighting a relationship between ovarian hormones and schizophrenia. To summarise, the preclinical data demonstrated in this thesis may offer more clinical insight into the importance of considering both estradiol and progesterone in schizophrenia pathophysiology during adolescence and adulthood. Further investigation in this area of research may help to yield novel therapeutic interventions