Sex Differences In Schizophrenia Research Articles

Sex affects transcriptional associations with schizophrenia across the dorsolateral prefrontal cortex, hippocampus, and caudate nucleus

Schizophrenia is a complex neuropsychiatric disorder with sexually dimorphic features, including differential symptomatology, drug responsiveness, and male incidence rate. Prior large-scale transcriptome analyses for sex differences in schizophrenia have focused on the prefrontal cortex. Analyzing BrainSeq Consortium data (caudate nucleus: n = 399, dorsolateral prefrontal cortex: n = 377, and hippocampus: n = 394), we identified 831 unique genes that exhibit sex differences across brain regions, enriched for immune-related pathways. We observed X-chromosome dosage reduction in the hippocampus of male individuals with schizophrenia. Our sex interaction model revealed 148 junctions dysregulated in a sex-specific manner in schizophrenia. Sex-specific schizophrenia analysis identified dozens of differentially expressed genes, notably enriched in immune-related pathways. Finally, our sex-interacting expression quantitative trait loci analysis revealed 704 unique genes, nine associated with schizophrenia risk. These findings emphasize the importance of sex-informed analysis of sexually dimorphic traits, inform personalized therapeutic strategies in schizophrenia, and highlight the need for increased female samples for schizophrenia analyses.

Relationship of serum estradiol and progesterone with symptoms and sex difference in schizophrenia: A cross-sectional study in Iran.

Schizophrenia is a devastating disease characterized by frequent relapses, cognitive decline, and emotional and functional disability, with unknown causes. The phenomenology and clinical course of schizophrenic disorders are different between the two genders, which is thought to be related mainly to the effects of steroid sex hormones on the nervous system. Regarding inconsistencies in the studies, we aimed to compare the levels of estradiol and progesterone between schizophrenia patients and healthy individuals. This cross-sectional study was conducted on 66 patients referred to the specialized clinical psychiatric ward of a teaching hospital in the north of Iran, for 5 months in 2021. Thirty-three schizophrenia patients confirmed by a psychiatrist based on DSM5 criteria were included in the case group, and 33 individuals without a psychiatric disease were included in the control group. We completed a demographic information checklist for each patient, along with the Simpson-Angus extrapyramidal side effect scale (SAS) for drug side effects and the positive and negative syndrome scale (PANSS) for the severity of the disease symptoms. Then, a 3-ml blood sample was taken from each participant to determine the serum levels of estradiol and progesterone. The data were analyzed by SPSS16 software. Thirty-four (51.5%) and 32 (48.5%) participants in this study were male and female, respectively. The mean serum level of estradiol was 22.33 ± 13.65 pm/dl in schizophrenia patients and 29.36 ± 21.32 pm/dl in the control group, showing no significant difference between the two groups (P = 0.4). However, the mean serum level of progesterone was significantly lower in schizophrenia patients (0.37 ± 1.39 pm/dl) than in control subjects (3.15 ± 5.73 pm/dl) (P < 0.001). The PANSS and SAS scores were not significantly correlated with the level of sex hormones (P > 0.05). Serum estradiol and progesterone levels based on sex significantly differed between the two groups (except for female estradiol). Considering the hormonal differences between schizophrenia patients and control subjects, determining hormonal levels in these patients and using complementary hormonal therapies with estradiol or similar compounds can be beneficial as the starting point of schizophrenia treatment, where therapeutic responses can draw the future developmental framework.

Adolescent raloxifene treatment in females prevents cognitive deficits in a neurodevelopmental rodent model of schizophrenia

The existence of sex differences in schizophrenia is a well documented phenomenon which led to the hypothesis that female sex hormones are neuroprotective and hence responsible for the more favorable disease characteristics seen in women. The current study sought to investigate the effects of estrogen-like agents administered during early adolescence on behavioral outcomes in adulthood using the neurodevelopmental maternal immune activation (MIA) rodent model of schizophrenia. Female MIA offspring were administered during the asymptomatic period of adolescence with either 17β-estradiol, raloxifene or saline and were tested in late adolescence and adulthood for schizophrenia-related behavioral performance. We report here that whereas adult female MIA offspring exhibited cognitive deficits in the form of retarded spatial learning, the administration of raloxifene during adolescence was sufficient in preventing these deficits and resulted in intact performance in the MIA group.

In-depth investigations of the molecular basis underlying sex differences among middle-aged and elderly schizophrenia populations.

Sex can influence almost all aspects of schizophrenia. However, the molecular mechanisms underlying sex differences in schizophrenia remain poorly understood. In this project, the dataset GSE107638 containing neuronal RNA-seq data and age/sex information of individuals with or without schizophrenia were retrieved. Schizophrenia samples were divided into young male (M-1), young female (F-1), middle-aged and elderly male (M-2) and middle-aged and elderly female (F-2) groups. Next, green/yellow/turquoise modules related to the M-2 trait and turquoise module correlated with the F-2 trait were identified by weighted correlation network analysis (WGCNA) analysis (soft thresholding power: 13; min module size: 200). Crucial genes in the M-2 green, M-2 turquoise and F-2 turquoise modules were identified by WGCNA, gene significance/module membership, and protein-protein interaction (PPI) analysis. Moreover, 2067 and 934 differentially expressed genes (|log2 fold-change| ≥0.58 and P-value < 0.05) in M-2 and F-2 schizophrenia subgroups versus same-age and same-sex counterparts were identified, respectively. Additionally, 82 core genes in the M-2 turquoise module and 4 hub genes in the F-2 turquoise module were differentially expressed in M-2 and F-2 schizophrenia subgroups versus their counterparts, respectively. Among the 82 hub genes, 15 genes were found to be correlated with neuronal development by the Kyoto Encyclopedia of Genes and Genomes enrichment analysis. Also, 2 potential PPI networks related to neuronal development were identified. Taken together, multiple potential hub genes and 2 potential neurobiological networks related to schizophrenia sex differences and disease progression were identified among middle-aged and elderly schizophrenia populations.

S-SCAM inhibits Axin-dependent synaptic function of GSK3\u03b2 in a sex-dependent manner

S-SCAM/MAGI-2 gene duplication is associated with schizophrenia (SCZ). S-SCAM overexpression in the forebrain induces SCZ-like phenotypes in a transgenic (Tg) mouse model. Interestingly, S-SCAM Tg mice show male-specific impairments in synaptic plasticity and working memory. However, mechanisms underlying the sex-specific deficits remain unknown. Here we report that S-SCAM Tg mice have male-specific deficits in synaptic GSK3β functions, as shown by reduced synaptic protein levels and increased inhibitory phosphorylation of GSK3β. This GSK3β hyper-phosphorylation was associated with increased CaMKII activities. Notably, synaptic levels of Axin1, to which GSK3β binds in competition with S-SCAM, were also reduced in male S-SCAM Tg mice. We demonstrated that Axin-binding is required for the S-SCAM overexpression-induced synaptic GSK3β reduction. Axin stabilization using XAV939 rescued the GSK3β deficits and restored the temporal activation of GSK3β during long-term depression in S-SCAM overexpressing neurons. Interestingly, synaptic Axin2 levels were increased in female S-SCAM Tg mice. Female sex hormone 17β-estradiol increased Axin2 expression and increased synaptic GSK3β levels in S-SCAM overexpressing neurons. These results reveal the role of S-SCAM in controlling Axin-dependent synaptic localization of GSK3β. Moreover, our studies point out the pathological relevance of GSK3β hypofunction found in humans and contribute to understanding the molecular underpinnings of sex differences in SCZ.

Sex-specific effects of polygenic risk for schizophrenia on lifespan cognitive functioning in healthy individuals

Polygenic risk for schizophrenia has been associated with lower cognitive ability and age-related cognitive change in healthy individuals. Despite well-established neuropsychological sex differences in schizophrenia patients, genetic studies on sex differences in schizophrenia in relation to cognitive phenotypes are scarce. Here, we investigated whether the effect of a polygenic risk score (PRS) for schizophrenia on childhood, midlife, and late-life cognitive function in healthy individuals is modified by sex, and if PRS is linked to accelerated cognitive decline. Using a longitudinal data set from healthy individuals aged 25–100 years (N = 1459) spanning a 25-year period, we found that PRS was associated with lower cognitive ability (episodic memory, semantic memory, visuospatial ability), but not with accelerated cognitive decline. A significant interaction effect between sex and PRS was seen on cognitive task performance, and sex-stratified analyses showed that the effect of PRS was male-specific. In a sub-sample, we observed a male-specific effect of the PRS on school performance at age 12 (N = 496). Our findings of sex-specific effects of schizophrenia genetics on cognitive functioning across the lifespan indicate that the effects of underlying disease genetics on cognitive functioning is dependent on biological processes that differ between the sexes.

Understanding sex differences in long-term outcomes after a first episode of psychosis

While sex differences in schizophrenia have long been reported and discussed, long-term sex differences in outcomes among first episode of psychosis (FEP) patients in terms of the efficacy of Early Intervention Services (EIS) has been an under-explored area. A total of 209 FEP patients (95 females and 114 males) were reassessed after a time window ranging from 8 to 16 years after their first contact with an EIS program (PAFIP) that we will call the 10-year PAFIP cohort. Multiple clinical, cognitive, functioning, premorbid, and sociodemographic variables were explored at 1-year, 3-year and 10-year follow-ups. At first contact, females were older at illness onset, had higher premorbid adjustment and IQ, and were more frequently employed, living independently, and accompanied by a partner and/or children. Existence of a schizophrenia diagnosis, and cannabis and alcohol consumption were more probable among men. During the first 3 years, women showed a significantly better response to minimal antipsychotic dosages and higher rates of recovery than men (50% vs. 30.8%). Ten years later, more females continued living independently and had partners, while schizophrenia diagnoses and cannabis consumption continued to be more frequent among men. Females also presented a lower severity of negative symptoms; however, functionality and recovery differences did not show significant differences (46.7% vs. 34.4%). Between the 3- and 10-year follow-up sessions, an increase in dosage of antipsychotics was observed. These results suggest that the better outcomes seen among women during the first 3 years (while they were treated in an EIS) were in the presence of more favourable premorbid and baseline characteristics. After an average period of 10 years, with the only difference being in negative symptoms course, outcomes for women approximated those of men, drawing particular attention to the increase in dosage of antipsychotic medication once FEP patients were discharged from the EIS program towards community-based services. These findings help to pose the question of whether it is advisable to target sexes and lengthen EIS interventions.

Characterizing the Complexity of Weighted Networks via Graph Embedding and Point Pattern Analysis.

We propose a new metric to characterize the complexity of weighted complex networks. Weighted complex networks represent a highly organized interactive process, for example, co-varying returns between stocks (financial networks) and coordination between brain regions (brain connectivity networks). Although network entropy methods have been developed for binary networks, the measurement of non-randomness and complexity for large weighted networks remains challenging. We develop a new analytical framework to measure the complexity of a weighted network via graph embedding and point pattern analysis techniques in order to address this unmet need. We first perform graph embedding to project all nodes of the weighted adjacency matrix to a low dimensional vector space. Next, we analyze the point distribution pattern in the projected space, and measure its deviation from the complete spatial randomness. We evaluate our method via extensive simulation studies and find that our method can sensitively detect the difference of complexity and is robust to noise. Last, we apply the approach to a functional magnetic resonance imaging study and compare the complexity metrics of functional brain connectivity networks from 124 patients with schizophrenia and 103 healthy controls. The results show that the brain circuitry is more organized in healthy controls than schizophrenic patients for male subjects while the difference is minimal in female subjects. These findings are well aligned with the established sex difference in schizophrenia.

A new sex-specific underlying mechanism for female schizophrenia: accelerated skewed X chromosome inactivation

BackgroundX chromosome inactivation (XCI) is the mechanism by which the X-linked gene dosage is adjusted between the sexes. Evidence shows that many sex-specific diseases have their basis in X chromosome biology. While female schizophrenia patients often have a delayed age of disease onset and clinical phenotypes that are different from those of males, it is unknown whether the sex differences in schizophrenia are associated with X-linked gene dosage and the choice of X chromosome silencing in female cells. Previous studies demonstrated that sex chromosome aneuploidies may be related to the pathogeneses of some psychiatric diseases. Here, we examined the changes in skewed XCI in patients with schizophrenia.MethodsA total of 109 female schizophrenia (SCZ) patients and 80 age- and sex-matched healthy controls (CNTLs) were included in this study. We evaluated clinical features including disease onset age, disease duration, clinical symptoms by the Positive and Negative Syndrome Scale (PANSS) and antipsychotic treatment dosages. The XCI skewing patterns were analyzed by the methylation profile of the HUMARA gene found in DNA isolated from SCZ patient and CNTL leukocytes in the three age groups.ResultsFirst, we found that the frequency of skewed XCI in SCZ patients was 4 times more than that in the age- and sex-matched CNTLs (p < 0.01). Second, we found an earlier onset of severe XCI skewing in the SCZ patients than in CNTLs. Third, we demonstrated a close relationship between the severity of skewed XCI and schizophrenic symptoms (PANSS score ≥ 90) as well as the age of disease onset. Fourth, we demonstrated that the skewed XCI in SCZ patients was not transmitted from the patients’ mothers.LimitationsThe XCI skewing pattern might differ depending on tissues or organs. Although this is the first study to explore skewed XCI in SCZ, in the future, samples from different tissues or cells in SCZ patients might be important for understanding the impact of skewed XCI in this disease.ConclusionOur study, for the first time, investigated skewed XCI in female SCZ patients and presented a potential mechanism for the sex differences in SCZ. Our data also suggested that XCI might be a potential target for the development of female-specific interventions for SCZ.

Sex differences in the effect of maternal immune activation on cognitive and psychosis‐like behaviour in Long Evans rats

Maternal immune activation during pregnancy is associated with increased risk of development of schizophrenia in later life. There are sex differences in schizophrenia, particularly in terms of age of onset, course of illness and severity of symptoms. However, there is limited and inconsistent literature on sex differences in the effects of maternal immune activation on behaviour with relevance to schizophrenia. The aim of this study was therefore to investigate sex differences in the effects of maternal immune activation by treating Long Evans rats with poly(I:C) on gestational day 15. We compared adult male and female offspring on spatial working memory in the touchscreen trial-unique nonmatching-to-location task, pairwise discrimination and reversal learning, as well as on prepulse inhibition and psychotropic drug-induced locomotor hyperactivity. Male, but not female poly(I:C) offspring displayed a deficit in spatial working memory, particularly at the longer delay. Neither pairwise discrimination nor reversal learning showed an effect of poly(I:C), but female controls outperformed male controls in the reversal learning task. Significant reduction of prepulse inhibition and enhancement of acute methamphetamine-induced locomotor hyperactivity was found similarly in male and female poly(I:C) offspring. These results show that maternal immune activation induces a range of behavioural effects in the offspring, with sex specificity in the effects of maternal immune activation on some aspects of cognition, but not psychosis-like behaviour.

Chapter 20 - Schizophrenia spectrum and other psychotic disorders

Since its earliest conceptualization, schizophrenia has been considered a disorder of "young men." Contemporary research suggests that there are sex differences in schizophrenia that are both transdiagnostic and representative of general sex/gender differences across the psychopathology spectrum. This chapter selectively summarizes representative sex/gender differences in clinical expression, epidemiology, risk factors, treatment, as well as course and outcome in schizophrenia. The consistent sex differences found, such as onset age, generic brain anomalies, and hormonal involvement, are not specific to schizophrenia or necessarily to psychopathology. It is suggested that in working with those diagnosed as meeting the current criteria for schizophrenia, clinicians adopt a transdiagnostic framework informed by sex and gender role processes.

Sex influences in the preventive effects of N-acetylcysteine in a two-hit animal model of schizophrenia.

Schizophrenia (SCZ) is a neurodevelopmental disorder influenced by patient sex. Mechanisms underlying sex differences in SCZ remain unknown. A two-hit model of SCZ combines the exposure to perinatal infection (first-hit) with peripubertal unpredictable stress (PUS, second-hit). N-acetylcysteine (NAC) has been tested in SCZ because of the involvement of glutathione mechanisms in its neurobiology. We aim to investigate whether NAC administration to peripubertal rats of both sexes could prevent behavioral and neurochemical changes induced by the two-hit model. Wistar rats were exposed to polyinosinic:polycytidylic acid (a viral mimetic) or saline on postnatal days (PND) 5-7. On PND30-59 they received saline or NAC 220 mg/kg and between PND40-48 were subjected to PUS or left undisturbed. On PND60 behavioral and oxidative alterations were evaluated in the prefrontal cortex (PFC) and striatum. Mechanisms of hippocampal memory regulation such as immune expression of G protein-coupled estrogen receptor 1 (GPER), α7-nAChR and parvalbumin were also evaluated. NAC prevented sensorimotor gating deficits only in females, while it prevented alterations in social interaction, working memory and locomotor activity in both sexes. Again, in rats of both sexes, NAC prevented the following neurochemical alterations: glutathione (GSH) and nitrite levels in the PFC and lipid peroxidation in the PFC and striatum. Striatal oxidative alterations in GSH and nitrite were observed in females and prevented by NAC. Two-hit induced hippocampal alterations in females, namely expression of GPER-1, α7-nAChR and parvalbumin, were prevented by NAC. Our results highlights the influences of sex in NAC preventive effects in rats exposed to a two-hit schizophrenia model.

Sex differences in schizophrenia, bipolar disorder, and post-traumatic stress disorder: Are gonadal hormones the link?

In this review, we describe the sex differences in prevalence, onset, symptom profiles, and disease outcome that are evident in schizophrenia, bipolar disorder, and post-traumatic stress disorder. Women with schizophrenia tend to exhibit less disease impairment than men. By contrast, women with post-traumatic stress disorder are more affected than men. The most likely candidates to explain these sex differences are gonadal hormones. This review details the clinical evidence that oestradiol and progesterone are dysregulated in these psychiatric disorders. Notably, existing data on oestradiol, and to a lesser extent, progesterone, suggest that low levels of these hormones may increase the risk of disease development and worsen symptom severity. We argue that future studies require a more inclusive, considered analysis of gonadal steroid hormones and the intricacies of the interactions between them, with methodological rigour applied, to enhance our understanding of the roles of steroid hormones in psychiatric disorders. LINKED ARTICLES: This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc.

EFFECT OF SEX DIFFERENCES ON INFLAMMATION IN SCHIZOPHRENIA: RELATIONSHIPS WITH SLEEP DISTURBANCES, COGNITIVE FUNCTIONING, AND CARDIOMETABOLIC RISK

Introduction Persons with schizophrenia (SZ) have life expectancies that are 15-20 years shorter than the general population, primarily due to cardiovascular-related deaths. In addition to premature mortality, persons with SZ have high rates of disability largely due to cognitive deficits. While cardiometabolic risk as well as cognition are known to be associated with poor sleep and inflammation in the general population, this has not been systematically examined in persons with SZ, although SZ is associated with inflammatory pathology and sleep disturbances that predate the use of antipsychotic medications and accumulation of poor lifestyle habits. Within the general population, women have higher inflammatory marker levels and are more likely to have sleep disturbances and cognitive decline as they age. This study examines the link between sleep, cognition and cardiometabolic risk within persons with SZ, focusing on sex differences. Methods The sample included 152 subjects with SZ (DSM-IV-TR criteria) and 141 non-psychiatric comparison (NC) subjects (age range 26 to 65 years; mean 48), with comparable sex and race distribution. We examined sleep (self-reported duration and quality), cardiometabolic risk [Framingham 10-year Risk of cardiovascular disease, high-sensitivity C-reactive protein or hs-CRP, insulin resistance using the Homeostatic Model of Assessment for Insulin Resistance or HOMA-IR], cognition [executive functioning (D-KEFS), overall cognitive functioning (TICS - modified)]; and blood-based inflammatory markers (TNF-a, IL-6, IL-10). In a subset of subjects, we also examined objective measures of sleep (total sleep time (TST), wake after sleep onset (WASO), latency, and efficiency) using wrist-worn actigraphy. The sleep-inflammation-cardiometabolic risk links were examined using Spearman's correlations and general linear models with a backward elimination approach to trim the models. Results The SZ group reported higher total sleep time and worse sleep quality, worse cardiometabolic risk, and increased levels of inflammatory markers compared to NCs. Within the SZ group, SZ men had higher Framingham Risk, lower hs-CRP and IL-6 levels, as well as better overall cognitive functioning than SZ women (Cohen's d = -0.65, 0.48, 0.38, and -0.33, respectively.) In SZ men, shorter sleep duration and poor sleep quality was associated with higher IL-6 and TNF-a levels and better executive functioning. Within the SZ group, Framingham Risk was associated with sex (as expected), age, IL-6, TNF-a, and overall cognition such that younger women with lower levels of IL-6 and TNF-a as well as better overall cognition had lower Framingham Risk (partial eta-squared = 0.19, 0.27, 0.03, 0.04, and 0.02, respectively). The levels of hs-CRP and HOMA-IR were not associated with sex. The levels of hs-CRP was associated with age, IL-6 and overall cognition (partial eta-squared = 0.02, 0.19, and 0.08, respectively). HOMA-IR was associated with age, duration of sleep, sleep quality, IL-6, and overall cognition such that younger persons with longer sleep duration, better sleep quality, lower inflammation and better cognitive functioning had less insulin resistance (partial eta-squared = 0.02, 0.02, 0.05, 0.03, and 0.08, respectively.) Objective measures of sleep disturbances (TST, WASO) were associated with HOMA-IR, executive functioning, as well as levels of hs-CRP and IL-6. Conclusions There are complexities in the associations of different inflammatory biomarkers with clinically meaningful measures of sleep, cardiometabolic health and cognition that reveal sex differences in SZ. Self-reported sleep disturbances and increased inflammation are associated in persons with SZ. Levels of inflammation and sleep disturbances, and their relationships, were sex-dependent in the SZ group, but not the NC group. Longitudinal examination of the sleep-inflammation links, their contribution to clinical outcomes, and the relationship with objective sleep measures and sex-specific factors is warranted. This research was funded by This study was supported, in part, by the National Institutes of Health (grant R01MH094151-01 to DVJ [PI]), by the National Institute of Mental Health T32 Geriatric Mental Health Program (grant MH019934 to DVJ [PI]), by the Stein Institute for Research on Aging at the University of California San Diego, and by the National Institutes of Health, Grant UL1TR001442 of CTSA funding. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Testosterone and schizophrenia: A clinical review

<br>The relationship between testosterone and psychiatric disorders has been a long-standing one. The sex difference in schizophrenia has triggered to better understand the role that testosterone plays in the unfolding and clinical presentation of this psychotic disorder. DHEA and testosterone are found to influence dopaminergic, glutamatergic and GABAergic neurotransmission systems that are believed to play a role in the pathophysiology of schizophrenia. The onset of schizophrenia in males, most frequently encountered during adolescence, is also characterized by an increase in testosterone levels. Some studies have also observed lower testosterone levels in adult males with schizophrenia (or psychosis) compared to healthy controls.<br>

The PPARα agonist fenofibrate attenuates disruption of dopamine function in a maternal immune activation rat model of schizophrenia.

SummaryAimsPrenatal maternal immune activation (MIA) is associated with a risk to develop schizophrenia and affects dopamine systems in the ventral tegmental area (VTA), key region in the neurobiology of psychoses. Considering the well‐described sex differences in schizophrenia, we investigated whether sex affects MIA impact on dopamine system and on schizophrenia‐related behavioral phenotype. Furthermore, considering peroxisome proliferator‐activated receptor‐α (PPARα) expression in the CNS as well as its anti‐inflammatory and neuroprotective properties, we tested if PPARα activation by prenatal treatment with a clinically available fibrate (fenofibrate) may mitigate MIA‐related effects.MethodsWe induced MIA in rat dams with polyriboinosinic‐polyribocytidylic acid (Poly I:C) and assessed prepulse inhibition and dopamine neuron activity in the VTA by means of electrophysiological recordings in male and female preweaned and adult offspring.ResultsPoly I:C‐treated males displayed prepulse inhibition deficits, reduced number and firing rate of VTA dopamine neurons, and paired‐pulse facilitation of inhibitory and excitatory synapses. Prenatal fenofibrate administration attenuated detrimental effects induced by MIA on both the schizophrenia‐like behavioral phenotype and dopamine transmission in male offspring.ConclusionOur study confirms previous evidence that females are less susceptible to MIA and highlights PPARα as a potential target for treatments in schizophrenia.

Abstracts from the NIH Office of Research on Women's Health 2018 Annual BIRCWH Meeting – Building Interdisciplinary Research Careers in Women's Health November 28, 2018

Abstracts from the NIH Office of Research on Women's Health 2018 Annual BIRCWH Meeting – Building Interdisciplinary Research Careers in Women's Health November 28, 2018

Male increase in brain gene expression variability is linked to genetic risk for schizophrenia

Schizophrenia shows substantial sex differences in age of onset, course, and treatment response, but the biological basis of these effects is incompletely understood. Here we show that during human development, males show a regionally specific decrease in brain expression similarity compared to females. The genes modulating this effect were significantly co-expressed with schizophrenia risk genes during prefrontal cortex brain development in the fetal period as well as during early adolescence. This suggests a genetic contribution to a mechanism through which developmental abnormalities manifest with psychosis during adolescence. It further supports sex differences in brain expression variability as a factor underlying the well-established sex differences in schizophrenia.

Prenatal Immune Challenge in Mice Leads to Partly Sex-Dependent Behavioral, Microglial, and Molecular Abnormalities Associated with Schizophrenia.

Epidemiological studies revealed that environmental factors comprising prenatal infection are strongly linked to risk for later development of neuropsychiatric disorders such as schizophrenia. Considering strong sex differences in schizophrenia and its increased prevalence in males, we designed a methodological approach to investigate possible sex differences in pathophysiological mechanisms. Prenatal immune challenge was modeled by systemic administration of the viral mimic polyinosinic-polycytidylic acid (Poly I:C) to C57BL/6 mice at embryonic day 9.5. The consequences on behavior, gene expression, and microglia—brain immune cells that are critical for normal development—were characterized in male vs. female offspring at adulthood. The cerebral cortex, hippocampus, and cerebellum, regions where structural and functional alterations were mainly described in schizophrenia patients, were selected for cellular and molecular analyses. Confocal and electron microscopy revealed most pronounced differences in microglial distribution, arborization, cellular stress, and synaptic interactions in the hippocampus of male vs. female offspring exposed to Poly I:C. Sex differences in microglia were also measured under both steady-state and Poly I:C conditions. These microglial alterations were accompanied by behavioral impairment, affecting for instance sensorimotor gating, in males. Consistent with these results, increased expression of genes related to inflammation was measured in cerebral cortex and hippocampus of males challenged with Poly I:C. Overall, these findings suggest that schizophrenia's higher incidence in males might be associated, among other mechanisms, with an increased microglial reactivity to prenatal immune challenges, hence determining disease outcomes into adulthood.

A genomic lifespan program that reorganises the young adult brain is targeted in schizophrenia.

The genetic mechanisms regulating the brain and behaviour across the lifespan are poorly understood. We found that lifespan transcriptome trajectories describe a calendar of gene regulatory events in the brain of humans and mice. Transcriptome trajectories defined a sequence of gene expression changes in neuronal, glial and endothelial cell-types, which enabled prediction of age from tissue samples. A major lifespan landmark was the peak change in trajectories occurring in humans at 26 years and in mice at 5 months of age. This species-conserved peak was delayed in females and marked a reorganization of expression of synaptic and schizophrenia-susceptibility genes. The lifespan calendar predicted the characteristic age of onset in young adults and sex differences in schizophrenia. We propose a genomic program generates a lifespan calendar of gene regulation that times age-dependent molecular organization of the brain and mutations that interrupt the program in young adults cause schizophrenia.