Cortical expression of the RAPGEF1 gene in schizophrenia: investigating regional differences and suicide.

Rap guanine nucleotide exchange factor 1 (RAPGEF1) is involved in cell adhesion and neuronal migration. Previously we found lower RAPGEF1 mRNA levels in Brodmann's area (BA) 9 in subjects with schizophrenia compared to controls. This study aimed to determine whether RAPGEF1 expression was altered in other brain regions implicated in schizophrenia and whether this was associated with suicide. Using qPCR, we measured the levels of RAPGEF1 in post-mortem BA 8 and 44 from 27 subjects with schizophrenia and 26 non-psychiatric control subjects. To address the effect of antipsychotic treatments, Rapgef1 mRNA levels were measured in the cortex from rats treated with typical antipsychotic drugs. There was no difference in RAPGEF1 normalised relative expression levels in BA 8 or 44. However, in BA 8, schizophrenia subjects had higher raw Ct RAPGEF1 levels compared to controls. There were higher RAPGEF1 levels in suicide completers compared to non-suicide schizophrenia subjects in BA 8. Rapgef1 expression levels in the rat cortex did not vary with antipsychotic treatment. Our findings suggest changes in RAPGEF1 expression may be limited to the dorsolateral prefrontal cortex from subjects with schizophrenia. Further investigation of the function of RAPGEF1 may lead to a greater understanding of the pathophysiology of schizophrenia.

Progesterone: The neglected hormone in schizophrenia? A focus on progesterone-dopamine interactions.

Sex differences appear to be an important factor in schizophrenia. Women with schizophrenia tend to exhibit less disease impairment than men, typically presenting with a later age-at-onset, lower overall incidence and less severe symptoms. These observations underpin the estrogen hypothesis of schizophrenia, which postulates a protective role of estrogen against the development and severity of the disorder. While there has been significant attention placed on the impact of estrogens in schizophrenia, less consideration has been afforded to the role of progesterone, the other main female gonadal hormone. This narrative review discusses the role of progesterone as a neuroactive steroid and how it may be dysregulated in schizophrenia. Preclinical and molecular studies relevant to schizophrenia are discussed with a particular focus on the interactions between progesterone and the dopaminergic system. Notably, existing data on progesterone in relation to schizophrenia is inconsistent, with some studies suggesting a neuroprotective role for the hormone (e.g. animal models of cognitive dysfunction and positive symptoms), while other studies posit a disruptive impact of the hormone (e.g. negative correlations with symptom modulation in patients). This review aims to thoroughly address these discrepancies, concluding that altogether the data suggest that progesterone is a key modulator of central systems implicated in schizophrenia. On this basis, we argue that a more inclusive, considered effort of future studies to understand the intricacies of the interactions between progesterone and estrogen. Such an effort may enhance our understanding of the roles of sex hormones in schizophrenia, thus leading to avenues for novel therapeutic approaches.

A Role for Estrogen in Schizophrenia: Clinical and Preclinical Findings.

Gender differences in schizophrenia have been extensively researched and it is being increasingly accepted that gonadal steroids are strongly attributed to this phenomenon. Of the various hormones implicated, the estrogen hypothesis has been the most widely researched one and it postulates that estrogen exerts a protective effect by buffering females against the development and severity of the illness. In this review, we comprehensively analyse studies that have investigated the effects of estrogen, in particular 17ß-estradiol, in clinical, animal, and molecular research with relevance to schizophrenia. Specifically, we discuss the current evidence on estrogen dysfunction in schizophrenia patients and review the clinical findings on the use of estradiol as an adjunctive treatment in schizophrenia patients. Preclinical research that has used animal models and molecular probes to investigate estradiol's underlying protective mechanisms is also substantially discussed, with particular focus on estradiol's impact on the major neurotransmitter systems implicated in schizophrenia, namely, the dopamine, serotonin, and glutamate systems.