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Epidemiological evidence suggests that due to its high isoflavone (genistein and daidzein) content a diet rich in soy could protect against breast cancer, particularly tumours expressing oestrogen receptor alpha (ERα+). Isoflavones are weakly oestrogenic, and have other wide ranging cellular activities. Contradictory in vitro evidence means that isoflavones’ mechanism(s) of action remain to be elucidated. ERα+ MCF7 and ERα-/ERβ+ MDA-MB-231 cell proliferation and apoptosis were quantified at a range of achievable serum concentrations of genistein or daidzein (0.01nM to 31.6μM) with or without pre-/post-menopausal 17β-oestradiol (E2) levels (1nM and 1pM). Additionally, cell volume regulation and macroscopic K+ current modulation by isoflavones and E2 in MCF7 cells were investigated. In MCF7 cells isoflavones (≥1μM) induce apoptosis, even in the presence of E2, but this did not reverse the synergistic effect of postmenopausal E2 and isoflavones on proliferation. Isoflavones slightly reduced MDA-MB-231 proliferation at all concentrations, dropping dramatically at 31.6μM. This response was partially maintained in the presence of postmenopausal E2. Isoflavones also induced markers of apoptosis. Treating MCF7 with 1nM E2 or 1μM genistein resulted in cell swelling, and a significant increase in whole cell current (E2 only), indicating a proliferative response. Conversely, treatment with 31.6μM genistein resulted in shrinkage, and inhibition of outward K+ current (not statistically significant). Daidzein treatment inhibited current to a lesser extent. Co-treatment with K+ channel blockers indicated the hEAG channel as a potential molecular target of genistein in MCF7. These results suggest that in ERα+ breast cancers, isoflavones may act by inducing apoptosis, shrinkage, and inhibition of hEAG current. There was no evidence suggesting that isoflavones reduce E2-promoted ERα+ cancer cell proliferation. Importantly, the inhibition of K+ channel activity by isoflavones represents a novel target for anti-cancer therapies. However, even low levels of isoflavones may be beneficial chemotherapeutic agents against ERα-/ERβ+ breast cancer, indicating an urgent requirement for further characterization of the effects of isoflavones in these breast cancers.

Both schizophrenia and bipolar disorder are characterised by deficits in cognitive function, particularly in those executive functions subserved by the prefrontal cortex. In order to further our understanding of the neuropathophysiology of cognitive deficits in psychiatric disorders, this thesis examined structural and functional changes in the prefrontal cortex (PFC) in rodent models mimicking some aspects of schizophrenia and bipolar disorder. Chosen models were subchronic phencyclidine (PCP), chronic administration of corticosterone to flatten the glucocorticoid rhythm (CORT) and maternal immune activation (MIA). These models mimic glutamate hypofunction, hypothalamo-pituitary adrenal axis dysfunction and maternal infection, respectively. Behavioural studies established that PCP induced a selective deficit in attentional set shifting whilst CORT and MIA induced reversal learning deficits. In vitro electrophysiological studies established a novel model for measuring synaptic transmission in the infralimbic (IL) region of the medial prefrontal cortex (mPFC). Synaptic transmission was shown to be mediated by glutamate and γ-aminobutyric acid (GABA) and to be subject to inhibitory modulation by serotonin (5-HT) and noradrenaline (NA). Differential changes in both basal synaptic transmission and in the monoaminergic modulation of synaptic transmission were evident in the three animal models. Immunohistochemical studies showed that the three animal models induced differential changes in the numbers of particular subtypes of GABAergic interneurones, suggesting that GABAergic activity in the mPFC was altered. These studies demonstrate that models of select features of psychiatric disorders, glutamate hypofunction, HPA axis dysfunction, and prenatal infection, induce deficits in executive function present in psychiatric disorders. These differential behavioural outcomes might be explained by differential changes in synaptic transmission in the mPFC and in the expression of GABAergic interneurones in the mPFC induced in the three models.