Brain-derived neurotrophic factor (BDNF) has a primary role in neuronal development, differentiation and plasticity in both the developing and adult brain. A single-nucleotide polymorphism in the proregion of BDNF, termed the Val66Met polymorphism, results in deficient subcellular translocation and activity-dependent secretion of BDNF, and has been associated with impaired neurocognitive function in healthy adults and in the incidence and clinical features of several psychiatric disorders. Research investigating the Val66Met polymorphism has increased markedly in the past decade, and a gap in integration exists between and within academic subfields interested in the effects of this variant. Here we comprehensively review the role and relevance of the Val66Met polymorphism in psychiatric disorders, with emphasis on suicidal behavior and anxiety, eating, mood and psychotic disorders. The cognitive and molecular neuroscience of the Val66Met polymorphism is also concisely reviewed to illustrate the effects of this genetic variant in healthy controls, and is complemented by a commentary on the behavioral neuroscience of BDNF and the Val66Met polymorphism where relevant to specific disorders. Lastly, a number of controversies and unresolved issues, including small effect sizes, sampling of allele inheritance but not genotype and putative ethnicity-specific effects of the Val66Met polymorphism, are also discussed to direct future research.

IntroductionIn the last decade or so, our knowledge of the roles of the steroids referred to as 'sex hormones' namely testosterone and estradiol, has undergone a quiet revolution. In the first place, models of androgen and estrogen insufficiency, whether they be natural or engineered, have revealed new and unexpected roles for sex steroids, some of which have nothing to do with reproduction.Furthermore both categories of steroid have roles in both sexes which blunts the definition of the terms 'androgen' and 'estrogen'. Secondly, the gradual acceptance of the role of local steroid hormone action, particularly as it applies in postmenopausal women and in men, provides new insights into the significance of paracrine and intracrine actions, and requires a re-evaluation of the importance of circulating steroid hormone levels. This article will attempt to review both of these developments, particularly in the context of the work of this laboratory on the aromatase knock-out (ArKO) mouse and the role of local aromatase expression within the breast and breast cancer. The concept of local estrogen biosynthesisModels of estrogen insufficiency have revealed new and unexpected roles for estrogens in both males and females. These models include natural mutations in the aromatase gene, as well as mouse knockouts of aromatase and the estrogen receptors (1)(2)(3)(4)(5)(6) . In addition there is one man described with a natural mutation in the ERα (7) . Some of the roles of estrogens apply equally to males and females and do not relate to reproduction, for example the bone, vascular and Metabolic Syndrome phenotypes.In postmenopausal women and in men, estradiol does not appear to function as a circulating hormone, instead it is synthesised in a number of extragonadal sites such as breast, brain and bone where its actions are mainly at the local 2 level as a paracrine or intracrine factor. Thus in postmenopausal women and in men, circulating estrogens are not the drivers of estrogen action, rather they reflect the metabolism of estrogens formed in these extragonadal sites, they are reactive rather than proactive (8) . Importantly, estrogen biosynthesis in these sites depends on a circulating source of androgenic precursors such as testosterone. Table 1 shows the plasma steroid levels in postmenopausal women and in men. As can be seen, the levels of estrone and estradiol in the plasma of postmenopausal women are extremely low, lower in fact than those in the circulation of men; and moreover the levels of circulating testosterone are an order of magnitude greater than those of estrogens in postmenopausal women.This in itself would suggest that circulating testosterone is better placed to serve as a precursor of estradiol in target tissues than is circulating estradiol.On the other hand, the levels of testosterone in the blood of men are an order of magnitude higher than those of women. Significantly, levels of DHEA and DHEAS in the blood of both men and women are orders of magnitude higher than those of the circulating active ste...

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Post-mortem studies have demonstrated reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus of schizophrenia and major depression patients. The "two hit" hypothesis proposes that two or more major disruptions at specific time points during development are involved in the pathophysiology of these mental illnesses. However, the role of BDNF in these "two hit" effects is unclear. Our aim was to behaviorally characterize a "two hit" rat model of developmental stress accompanied by an in-depth assessment of BDNF expression and signalling. Wistar rats were exposed to neonatal maternal separation (MS) stress and/or adolescent/young-adult corticosterone (CORT) treatment. In adulthood, models of cognitive and negative symptoms of mental illness were analyzed. The hippocampus was then dissected into dorsal (DHP) and ventral (VHP) regions and analyzed by qPCR for exon-specific BDNF gene expression or by Western blot for BDNF protein expression and downstream signaling. Male "two hit" rats showed marked disruptions in short-term spatial memory (Y-maze) which were absent in females. However, female "two hit" rats showed signs of anhedonia (sucrose preference test), which were absent in males. Novel object recognition and anxiety (elevated plus maze) were unchanged by either of the two "hits". In the DHP, MS caused a male-specific increase in BDNF Exons I, II, IV, VII, and IX mRNA but a decrease in mature BDNF and phosphorylated TrkB (pTrkB) protein expression in adulthood. In the VHP, BDNF transcript expression was unchanged; however, in female rats only, MS significantly decreased mature BDNF and pTrkB protein expression in adulthood. These data demonstrate that MS causes region-specific and sex-specific long-term effects on BDNF expression and signaling and, importantly, mRNA expression does not always infer protein expression. Alterations to BDNF signaling may mediate the sex-specific effects of developmental stress on anhedonic behaviors.

Sex steroid hormones and neurotrophic factors are involved in pruning and shaping the adolescent brain and have been implicated in the pathogenesis of neurodevelopmental disorders, including mental illness. We aimed to determine the association between altered levels of sex steroid hormones during adolescent development and neurotrophic signalling in the C57Bl/6 mouse. We first performed a week by week analysis from pre-pubescence to adulthood in male and female C57Bl/6 mice, measuring serum levels of testosterone and oestradiol in conjunction with western blot analysis of neurotrophin expression in the forebrain and hippocampal regions. Second, we manipulated adolescent sex steroid hormone levels by gonadectomy and hormone replacement at the pre-pubescent age of 5 weeks. Young-adult forebrain and hippocampal neurotrophin expression was then determined. Male mice showed significant changes in brain-derived neurotrophic factor (BDNF) expression in the forebrain regions during weeks 7-10, which corresponded significantly with a surge in serum testosterone. Castration and testosterone or di-hydrotestosterone replacement experiments revealed an androgen receptor-dependent effect on BDNF-tyrosine kinase (Trk) B signalling in the forebrain and hippocampal regions during adolescence. Female mice showed changes in BDNF-TrkB signalling at a much earlier time point (weeks 4-8) in the forebrain and hippocampal regions and these did not correspond with changes in serum oestradiol. Ovariectomy actually increased BDNF expression but decreased TrkB phosphorylation in the forebrain regions. 17β-Oestradiol replacement had no effect, suggesting a role for other ovarian hormones in regulating BDNF-TrkB signalling in the adolescent female mouse brain. These results suggest the differential actions of sex steroid hormones in modulating BDNF-TrkB signalling during adolescence. These data provide insight into how the male and female brain changes in response to altered levels of circulating sex steroid hormones and could help to explain some of the developmental sex differences in the pathogenesis of neurodevelopmental disorders, including mental illness.

Schizophrenia is a severe psychiatric disorder with a complex and variable set of symptoms. Both genetic and environmental mechanisms are involved in the development of the illness and lead to structural and neurochemical abnormalities in the brain. An intriguing facet of schizophrenia is sex differences, which have been described for nearly all features of the illness, including the peak age of onset, symptoms and treatment response. The ovarian hormone, estrogen, may be protective against schizophrenia and evidence is accumulating that estrogen may exert this effect via an interaction with brain-derived neurotrophic factor (BDNF). Both estrogen and BDNF have trophic effects on the developing brain and promote synaptic plasticity and maintain neurons well into adulthood. Major neurotransmitter systems including dopaminergic, serotonergic and glutamatergic pathways are modulated and supported by estrogen and BDNF. Despite their commonalities, estrogen and BDNF have mostly been examined independently but increasing evidence suggests an interaction between the two in brain regions pertinent to schizophrenia. This review will focus on the role of estrogen and BDNF in clinical and animal studies of schizophrenia. We include animal models of neurotransmitter dysfunction and genetic manipulation to show how estrogen may provide a protective effect in schizophrenia, including through mediating BDNF expression and activity. This posited estrogen-BDNF interaction could play a key role in modulating sex-dependent results reported in animal work as well as sex differences in clinical aspects of schizophrenia.

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