The role of steroid hormones in schizophrenia: unravelling the mechanism of 17-beta estradiol and raloxifene on cognitive function

© 2016 Dr. Anna SchroederThe glycoprotein reelin is integral for brain development and maintaining synaptic plasticity, and its expression is reduced in schizophrenia brains. Whether stress, a risk factor for schizophrenia, is mediated by altered reelin levels is unknown. Here, we showed that adolescent treatment with corticosterone (CORT), the major stress hormone, in a reelin heterozygous mouse model, induced hippocampal-dependent cognitive deficits in both male and female mice. Interestingly, female mice showed sex-specific molecular changes in the dorsal hippocampus after CORT treatment. This suggests a significant role of estrogens in mediating stress responses and cognition. One mechanism through which estrogens, particularly 17β-estradiol (E2), the most potent of the estrogens, may regulate cognitive function is through its ability to affect the number of parvalbumin (PV)-containing GABAergic interneurons. PV-interneurons are reduced in the brain of schizophrenia patients. In our previous study, ovariectomy (OVX) in mice reduced the number of hippocampal PV-interneurons which was accompanied by hippocampus-dependent memory impairment. Both neuron reduction and cognitive deficits were prevented by simultaneous E2 replacement after OVX. Due to the significant role of PV-interneurons in generating neuronal oscillations in the gamma frequency range, a vital component required for cognition, we investigated whether E2 can mediate gamma oscillations which would explain its influence on cognition. We further scrutinized whether raloxifene, a selective estrogen receptor modulator, has a similar effect on cognition as E2. Raloxifene has been shown to improve cognitive performance in schizophrenia patients and constitutes a safer treatment option as opposed to E2 due to its absence of peripheral side effects. We recorded electrical brain activities in the dorsal hippocampus of control, OVX mice or OVX mice with E2 or raloxifene implants both at baseline and during Y-maze, a hippocampal-dependent spatial memory task. While gamma-band oscillations were significantly increased in the control mice when placed in a novel environment (Y-maze), this increase was absent in OVX mice. E2 as well as raloxifene replacement prevented this deficit. This indicates that both E2 and raloxifene can regulate gamma oscillations in the dorsal hippocampus during exploration of a novel space. Moreover, OVX mice showed a significant reduction in gamma oscillations, specifically during decision making, which was accompanied by a significant deficit in short-term memory. E2 and raloxifene replacement rescued these deficits. This suggests that both E2 and raloxifene regulate spatial memory via specifically regulating hippocampal gamma oscillations during decision making. In agreement with this data we further demonstrated that raloxifene was able to recover gamma oscillations during decision making in the Polyinositic:polycitidylic acid (poly(I:C))-induced maternal immune activation mouse model of schizophrenia. Overall, these results suggest that raloxifene modulates hippocampus-dependent memory via preserving gamma oscillations through its conservation of PV-interneurons; a mechanism that most likely explains the beneficial effect of raloxifene on cognitive performance in schizophrenia patients. This aids understanding the mechanisms underlying the cognitive aspect of schizophrenia, but more importantly, strengthens the case of raloxifene as an adjunctive therapeutic option in this disorder