Increased Parenchymal Macrophages are associated with decreased Tyrosine Hydroxylase mRNA levels in the Substantia Nigra of people with Schizophrenia and Bipolar Disorder.

Increased activation of inflammatory macrophages and altered expression of dopamine markers are found in the midbrains of people with schizophrenia (SZ). The relationship of midbrain macrophages to dopamine neurons has not been explored, nor is it known if changes in midbrain macrophages are also present in bipolar disorder (BD) or major depressive disorder (MDD). Herein, we determined whether there were differences in CD163+ cell density in the Substantia Nigra (SN), and cerebral peduncles (CP) of SZ, BD, and MDD compared to controls (CTRL). We also analyzed whether CD163 protein and dopamine-synthesizing enzyme tyrosine hydroxylase (TH) mRNA levels differed among diagnostic groups and if they correlated with the density of macrophages. Overall, perivascular CD163+ cell density was higher in the gray matter (SN) than in the white matter (CP). Compared to CTRL, we found increased density of parenchymal CD163+ cells in the SN of the three psychiatric groups and increased CD163 protein levels in SZ. CD163 protein was positively correlated with density of perivascular CD163+ cells. TH mRNA was reduced in SZ and BD and negatively correlated with parenchymal CD163+ cell density. We provide the first quantitative and molecular evidence of an increase in the density of parenchymal macrophages in the midbrain of major mental illnesses and show that the presence of these macrophages may negatively impact dopaminergic neurons.

Antipsychotic-induced prolactin elevation in premenopausal women with schizophrenia: associations with estrogen, disease severity and cognition.

PURPOSE: Antipsychotic-induced prolactin elevation may impede protective effects of estrogens in women with schizophrenia-spectrum disorders (SSD). Our study sought to confirm whether the use of prolactin-raising antipsychotics is associated with lower estrogen levels, and to investigate how estrogen and prolactin levels relate to symptom severity and cognition in premenopausal women with SSD. METHODS: This cross-sectional study included 79 premenopausal women, divided in three groups of women with SSD treated with prolactin-sparing antipsychotics (n = 21) or prolactin-raising antipsychotics (n = 27), and age-matched women without SSD (n = 31). Circulating 17ß-estradiol was compared among groups. In patients, we assessed the relationship between prolactin and 17ß-estradiol, and the relationships of these hormones to symptom severity and cognition, using correlation analyses and backward regression models. RESULTS: In women receiving prolactin-raising antipsychotics, 17ß-estradiol levels were lower as compared to both other groups (H(2) = 8.34; p = 0.015), and prolactin was inversely correlated with 17ß-estradiol (r=-0.42, p = 0.030). In the prolactin-raising group, 17ß-estradiol correlated positively with verbal fluency (r = 0.52, p = 0.009), and 17ß-estradiol and prolactin together explained 29% of the variation in processing speed (ß17ß-estradiol = 0.24, ßprolactin = -0.45, F(2,25) = 5.98, p = 0.008). In the prolactin-sparing group, 17ß-estradiol correlated negatively with depression/anxiety (r = -0.57, p = 0.014), and together with prolactin explained 26% of the variation in total symptoms (ß17ß-estradiol = -0.41, ßprolactin = 0.32, F(2,18) = 4.44, p = 0.027). CONCLUSIONS: In women with SSD, antipsychotic-induced prolactin elevation was related to lower estrogen levels. Further, estrogens negatively correlated with symptom severity and positively with cognition, whereas prolactin levels correlated negatively with cognition. Our findings stress the clinical importance of maintaining healthy levels of prolactin and estrogens in women with SSD.

Molecular evidence of altered stress responsivity related to neuroinflammation in the schizophrenia midbrain.

Stress and inflammation are risk factors for schizophrenia. Chronic psychosocial stress is associated with subcortical hyperdopaminergia, a core feature of schizophrenia. Hyperdopaminergia arises from midbrain neurons, leading us to hypothesise that changes in stress response pathways may occur in this region. To identify whether transcriptional changes in glucocorticoid and mineralocorticoid receptors (NR3C1/GR, NR3C2/MR) or other stress signalling molecules (FKBP4, FKBP5) exist in schizophrenia midbrain, we measured gene expression in the human brain (N = 56) using qRT-PCR. We assessed whether alterations in these mRNAs were related to previously identified high/low inflammatory status. We investigated relationships between stress-related transcripts themselves, and between FKBP5 mRNA, dopaminergic, and glial cell transcripts in diagnostic and inflammatory subgroups. Though unchanged by diagnosis, GR mRNA levels were reduced in high inflammatory compared to low inflammatory schizophrenia cases (p = 0.026). We found no effect of diagnosis or inflammation on MR mRNA. FKBP4 mRNA was decreased and FKBP5 mRNA was increased in schizophrenia (p < 0.05). FKBP5 changes occurred in high inflammatory (p < 0.001), whereas FKBP4 changes occurred in low inflammatory schizophrenia cases (p < 0.05). The decrease in mRNA encoding the main stress receptor (GR), as well as increased transcript levels of the stress-responsive negative regulator (FKBP5), may combine to blunt the midbrain response to stress in schizophrenia when neuroinflammation is present. Negative correlations between FKBP5 mRNA and dopaminergic transcripts in the low inflammatory subgroup suggest higher levels of FKBP5 mRNA may also attenuate dopaminergic neurotransmission in schizophrenia even when inflammation is absent. We report alterations in GR-mediated stress signalling in the midbrain in schizophrenia.

The association of prolactin and gonadal hormones with cognition and symptoms in men with schizophrenia spectrum disorder: Divergent effects of testosterone and estrogen.

BACKGROUND: Certain antipsychotics elevate prolactin levels in patients with schizophrenia spectrum disorders (SSD), potentially affecting cognition, symptoms, and hormone levels. This study examines the association between prolactin, testosterone, and estrogen and cognition and symptoms in men with SSD, considering antipsychotic medication. METHODS: This cross-sectional study included 128 men with SSD and 44 healthy men from two trials. Patients were divided into a prolactin-sparing (n = 53) and prolactin-raising group (n = 75) based on antipsychotic medication. We examined the association between hormones (testosterone, estrogen and prolactin), and cognition and symptoms using backward linear regression. Three domains of cognition were assessed including: processing speed, verbal fluency, and working memory, while symptoms were measured using the Positive and Negative Syndrome Scale (PANSS). RESULTS: Prolactin levels were highest in the prolactin-raising group, followed by the control group, and lowest in the prolactin-sparing group (H = 45.279, p < .001). Testosterone and estrogen levels did not differ significantly between groups. In the prolactin-raising group, prolactin negatively correlated with testosterone (r(73) = -0.32, p = .005). Higher testosterone predicted better cognitive functioning (working memory: ß = 0.20, p = .007, verbal fluency: ß = 0.30, p = .001) and lower symptom scores (total: ß = -0.21, p = .001; negative: ß = -0.24, p = .002) in men with SSD. Conversely, higher estrogen levels related to slower processing speed (ß = -0.22, p < .001) and higher symptoms scores (ß = 0.23, p = .010) in men with SSD. CONCLUSION: The results suggest positive associations between testosterone and cognition and symptoms in men with SSD, while suggesting that high prolactin levels could relate to lower testosterone levels, possibly worsening cognition and symptoms in men with SSD.

RNA-sequencing suggests extracellular matrix and vasculature dysregulation could impair neurogenesis in schizophrenia cases with elevated inflammation.

A subgroup of schizophrenia cases with elevated inflammation have reduced neurogenesis markers and increased macrophage density in the human subependymal zone (SEZ; also termed subventricular zone or SVZ) neurogenic niche. Inflammation can impair neurogenesis; however, it is unclear which other pathways are associated with reduced neurogenesis. This research aimed to discover transcriptomic differences between inflammatory subgroups of schizophrenia in the SEZ. Total RNA sequencing was performed on SEZ tissue from schizophrenia cases, designated into low inflammation (n = 13) and high inflammation (n = 14) subgroups, based on cluster analysis of inflammation marker gene expression. 718 genes were differentially expressed in high compared to low inflammation schizophrenia (FDR p < 0.05) and were most significantly over-represented in the pathway 'Hepatic Fibrosis/Hepatic Stellate-Cell Activation'. Genes in this pathway relate to extracellular matrix stability (including ten collagens) and vascular remodelling suggesting increased angiogenesis. Collagen-IV, a key element of the basement membrane and fractones, had elevated gene expression. Immunohistochemistry revealed novel collagen-IV+ fractone bulbs within the human SEZ hypocellular gap. Considering the extracellular matrix's regulatory role in SEZ neurogenesis, fibrosis-related alterations in high inflammation schizophrenia may disrupt neurogenesis. Increased angiogenesis could facilitate immune cell transmigration, potentially explaining elevated macrophages in high inflammation schizophrenia. This discovery-driven analysis sheds light on how inflammation may contribute to schizophrenia neuropathology in the neurogenic niche.

Maternal immune activation and estrogen receptor modulation induce sex-specific dopamine-related behavioural and molecular alterations in adult rat offspring.

Dopamine dysregulation contributes to psychosis and cognitive deficits in schizophrenia that can be modelled in rodents by inducing maternal immune activation (MIA). The selective estrogen receptor (ER) modulator, raloxifene, can improve psychosis and cognition in men and women with schizophrenia. However, few studies have examined how raloxifene may exert its therapeutic effects in mammalian brain in both sexes during young adulthood (age relevant to most prevalent age at diagnosis). Here, we tested the extent to which raloxifene alters dopamine-related behaviours and brain transcripts in young adult rats, both control and MIA-exposed females and males. We found that raloxifene increased amphetamine (AMPH)-induced locomotor activity in female controls, and in contrast, raloxifene reduced AMPH-induced locomotor activity in male MIA offspring. We did not detect overt prepulse inhibition (PPI) deficits in female or male MIA offspring, yet raloxifene enhanced PPI in male MIA offspring. Whereas, raloxifene ameliorated increased startle responsivity in female MIA offspring. In the substantia nigra (SN), we found reduced Drd2s mRNA in raloxifene-treated female offspring with or without MIA, and increased Comt mRNA in placebo-treated male MIA offspring relative to placebo-treated controls. These data demonstrate an underlying dopamine dysregulation in MIA animals that can become more apparent with raloxifene treatment, and may involve selective alterations in dopamine receptor levels and dopamine breakdown processes in the SN. Our findings support sex-specific, differential behavioural responses to ER modulation in MIA compared to control offspring, with beneficial effects of raloxifene treatment on dopamine-related behaviours relevant to schizophrenia found in male MIA offspring only.

Single-Nucleus RNA-Seq Characterizes the Cell Types Along the Neuronal Lineage in the Adult Human Subependymal Zone and Reveals Reduced Oligodendrocyte Progenitor Abundance with Age.

The subependymal zone (SEZ), also known as the subventricular zone (SVZ), constitutes a neurogenic niche that persists during postnatal life. In humans, the neurogenic potential of the SEZ declines after the first year of life. However, studies discovering markers of stem and progenitor cells highlight the neurogenic capacity of progenitors in the adult human SEZ, with increased neurogenic activity occurring under pathological conditions. In the present study, the complete cellular niche of the adult human SEZ was characterized by single-nucleus RNA sequencing, and compared between four youth (age 16-22) and four middle-aged adults (age 44-53). We identified 11 cellular clusters including clusters expressing marker genes for neural stem cells (NSCs), neuroblasts, immature neurons, and oligodendrocyte progenitor cells. The relative abundance of NSC and neuroblast clusters did not differ between the two age groups, indicating that the pool of SEZ NSCs does not decline in this age range. The relative abundance of oligodendrocyte progenitors and microglia decreased in middle-age, indicating that the cellular composition of human SEZ is remodeled between youth and adulthood. The expression of genes related to nervous system development was higher across different cell types, including NSCs, in youth as compared with middle-age. These transcriptional changes suggest ongoing central nervous system plasticity in the SEZ in youth, which declined in middle-age.

Sex- and suicide-specific alterations in the kynurenine pathway in the anterior cingulate cortex in major depression.

Major depressive disorder (MDD) is a serious psychiatric disorder that in extreme cases can lead to suicide. Evidence suggests that alterations in the kynurenine pathway (KP) contribute to the pathology of MDD. Activation of the KP leads to the formation of neuroactive metabolites, including kynurenic acid (KYNA) and quinolinic acid (QUIN). To test for changes in the KP, postmortem anterior cingulate cortex (ACC) was obtained from the National Institute of Health NeuroBioBank. Gene expression of KP enzymes and relevant neuroinflammatory markers were investigated via RT-qPCR (Fluidigm) and KP metabolites were measured using liquid chromatography-mass spectrometry in tissue from individuals with MDD (n = 44) and matched nonpsychiatric controls (n = 36). We report increased IL6 and IL1B mRNA in MDD. Subgroup analysis found that female MDD subjects had significantly decreased KYNA and a trend decrease in the KYNA/QUIN ratio compared to female controls. In addition, MDD subjects that died by suicide had significantly decreased KYNA in comparison to controls and MDD subjects that did not die by suicide, while subjects that did not die by suicide had increased KYAT2 mRNA, which we hypothesise may protect against a decrease in KYNA. Overall, we found sex- and suicide-specific alterations in the KP in the ACC in MDD. This is the first molecular evidence in the brain of subgroup specific changes in the KP in MDD, which not only suggests that treatments aimed at upregulation of the KYNA arm in the brain may be favourable for female MDD sufferers but also might assist managing suicidal behaviour.

Toll-Like Receptor mRNA Levels in Schizophrenia: Association With Complement Factors and Cingulate Gyrus Cortical Thinning.

BACKGROUND AND HYPOTHESES: Previous studies revealed innate immune system activation in people with schizophrenia (SZ), potentially mediated by endogenous pathogen recognition receptors, notably Toll-like receptors (TLR). TLRs are activated by pathogenic molecules like bacterial lipopolysaccharides (TLR1 and TLR4), viral RNA (TLR3), or both (TLR8). Furthermore, the complement system, another key component of innate immunity, has previously been linked to SZ. STUDY DESIGN: Peripheral mRNA levels of TLR1, TLR3, TLR4, and TLR8 were compared between SZ and healthy controls (HC). We investigated their relationship with immune activation through complement expression and cortical thickness of the cingulate gyrus, a region susceptible to immunological hits. TLR mRNA levels and peripheral complement receptor mRNA were extracted from 86 SZ and 77 HC white blood cells; structural MRI scans were conducted on a subset. STUDY RESULTS: We found significantly higher TLR4 and TLR8 mRNA levels and lower TLR3 mRNA levels in SZ compared to HC. TLRs and complemental factors were significantly associated in SZ and HC, with the strongest deviations of TLR mRNA levels in the SZ subgroup having elevated complement expression. Cortical thickness of the cingulate gyrus was inversely associated with TLR8 mRNA levels in SZ, and with TLR4 and TLR8 levels in HC. CONCLUSIONS: The study underscores the role of innate immune activation in schizophrenia, indicating a coordinated immune response of TLRs and the complement system. Our results suggest there could be more bacterial influence (based on TLR 4 levels) as opposed to viral influence (based on TLR3 levels) in schizophrenia. Specific TLRs were associated with brain cortical thickness reductions of limbic brain structures.