Schizophrenia Research Laboratory

Randwick, Australia

Schizophrenia Research Laboratory

Randwick, Australia
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Allen K.M.,Schizophrenia Research Institute | Allen K.M.,Schizophrenia Research Laboratory | Allen K.M.,University of New South Wales | Fung S.J.,Schizophrenia Research Institute | And 8 more authors.
Hippocampus | Year: 2014

New neurons are continuously produced in the subgranular zone of the adult hippocampus and can modulate hippocampal plasticity across life. Adolescence is characterized by dramatic changes in sex hormone levels, and social and emotional behaviors. It is also an age for increased risk of psychiatric disorders, including schizophrenia, which may involve altered hippocampal neurogenesis. The extent to which testosterone and other testicular hormones modulate hippocampal neurogenesis and adolescent behavioral development is unclear. This study aimed to determine if removal of testicular hormones during adolescence alters neurogenesis in the male rhesus macaque hippocampus. We used stereology to examine levels of cell proliferation, cell survival and neuronal differentiation in late adolescent male rhesus macaques (4.6-yrs old) that had previously been gonadectomized or sham operated prior to puberty (2.4-yrs old). While the absence of adolescent testicular hormones had no effect on cell proliferation, cell survival was increased by 65% and indices of immature neuronal differentiation were increased by 56% in gonadectomized monkeys compared to intact monkeys. We show for the first time that presence of circulating testicular hormones, including testosterone, may decrease neuronal survival in the primate hippocampus during adolescence. Our findings are in contrast to existing studies in adults where testosterone tends to be a pro-survival factor and demonstrate that testicular hormones may reduce hippocampal neurogenesis during the age typical of schizophrenia onset. © 2013 Wiley Periodicals, Inc.

Catts V.S.,Schizophrenia Research Laboratory | Catts V.S.,University of New South Wales | Wong J.,University of Wollongong | Fillman S.G.,Schizophrenia Research Laboratory | And 5 more authors.
Australian and New Zealand Journal of Psychiatry | Year: 2014

Objective: While schizophrenia may have a progressive component, the evidence for neurodegenerative processes as indicated by reactive astrocytes is inconclusive. We recently identified a subgroup of individuals with schizophrenia with increased expression of inflammatory markers in prefrontal cortex, and hypothesized that this subgroup would also have reactive astrocytes. Method: We measured glial fibrillary acidic protein (GFAP) mRNA by quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR) and protein levels by immunoblotting in grey matter homogenate from 37 individuals with schizophrenia and 37 unaffected controls. We examined the morphology of GFAP-positive astrocytes in immunostained sections of middle frontal gyrus. We tested if GFAP expression or astrocyte morphology were altered in people with schizophrenia with increased expression of inflammatory markers. We used RNA-Seq data on a subset of patients and controls (n=20/group) to ascertain whether mRNA transcripts associated with astrogliosis were elevated in the individuals with active neuroinflammation. Results: GFAP (mRNA and protein) levels and astrocyte morphology were not significantly different between people with schizophrenia and controls overall. However, individuals with schizophrenia with neuroinflammation had increased expression of GFAP mRNA (t(33)=2.978, p=0.005), hypertrophic astrocyte morphology (÷2(2)=6.281, p=0.043), and statistically significant elevated expression of three mRNA transcripts previously associated with astrogliosis. Conclusions: We found clear evidence of astrogliosis in a subset of people with schizophrenia. We suggest that the lack of astrogliosis reported in previous studies may be due to cohort differences in aetiopathology, illness stage, treatment exposure, or a failure to examine subsets of people with schizophrenia. © The Royal Australian and New Zealand College of Psychiatrists 2014.

Fillman S.G.,Schizophrenia Research Institute | Fillman S.G.,Schizophrenia Research Laboratory | Fillman S.G.,University of New South Wales | Cloonan N.,University of Queensland | And 11 more authors.
Molecular Psychiatry | Year: 2013

Upregulation of the immune response may be involved in the pathogenesis of schizophrenia with changes occurring in both peripheral blood and brain tissue. To date, microarray technology has provided a limited view of specific inflammatory transcripts in brain perhaps due to sensitivity issues. Here we used SOLiD Next Generation Sequencing to quantify neuroimmune mRNA expression levels in the dorsolateral prefrontal cortex of 20 individuals with schizophrenia and their matched controls. We detected 798 differentially regulated transcripts present in people with schizophrenia compared with controls. Ingenuity pathway analysis identified the inflammatory response as a key change. Using quantitative real-time PCR we confirmed the changes in candidate cytokines and immune modulators, including interleukin (IL)-6, IL-8, IL-1β and SERPINA3. The density of major histocompatibility complex-II-positive cells morphologically resembling microglia was significantly increased in schizophrenia and correlated with IL-1β expression. A group of individuals, most of whom had schizophrenia, were found to have increased inflammatory mRNA expression. In summary, we have demonstrated changes in an inflammatory response pathway that are present in ∼40% of people diagnosed with schizophrenia. This suggests that therapies aimed at immune system attenuation in schizophrenia may be of direct benefit in the brain. © 2013 Macmillan Publishers Limited.

Sinclair D.,Schizophrenia Research Institute | Sinclair D.,Schizophrenia Research Laboratory | Sinclair D.,University of New South Wales | Sinclair D.,University of Pennsylvania | And 9 more authors.
Psychopharmacology | Year: 2014

Rationale: Adolescence is a developmental period of complex neurobiological change and heightened vulnerability to psychiatric illness. As a result, understanding factors such as sex and stress hormones which drive brain changes in adolescence, and how these factors may influence key neurotransmitter systems implicated in psychiatric illness, is paramount. Objectives: In this review, we outline the impact of sex and stress hormones at adolescence on dopamine neurotransmission, a signaling pathway which is critical to healthy brain function and has been implicated in psychiatric illness. We review normative developmental changes in dopamine, sex hormone, and stress hormone signaling during adolescence and throughout postnatal life, then highlight the interaction of sex and stress hormones and review their impacts on dopamine neurotransmission in the adolescent brain. Results and conclusions: Adolescence is a time of increased responsiveness to sex and stress hormones, during which the maturing dopaminergic neural circuitry is profoundly influenced by these factors. Testosterone, estrogen, and glucocorticoids interact with each other and have distinct, brain region-specific impacts on dopamine neurotransmission in the adolescent brain, shaping brain maturation and cognitive function in adolescence and adulthood. Some effects of stress/sex hormones on cortical and subcortical dopamine parameters bear similarities with dopaminergic abnormalities seen in schizophrenia, suggesting a possible role for sex/stress hormones at adolescence in influencing risk for psychiatric illness via modulation of dopamine neurotransmission. Stress and sex hormones may prove useful targets in future strategies for modifying risk for psychiatric illness. © 2014 The Author(s).

Oh D.H.,Hanyang University | Oh D.,CHA Medical University | Son H.,Hanyang University | Webster M.J.,Stanley Medical Research Institute | And 2 more authors.
Journal of Neural Transmission | Year: 2014

Previous human postmortem studies have shown that expression of glutamate transporters (SLC1A2 and SLC1A3) and gamma-aminobutyric acid-synthesizing enzyme [glutamic acid decarboxylase 1 (GAD1)] are reduced in the dorsolateral prefrontal cortex (dlPFC) in subjects with major depressive disorder (MDD). However, no studies have explored the association between these two molecules and its related biological processes in MDD because of limited postmortem sample availability. Data sharing using the Stanley neuropathology consortium integrative database (SNCID), a web-based tool that integrates datasets from the same postmortem brain samples, allowed us to reanalyze existing postmortem data efficiently. We found two datasets where the mRNA levels of GAD1 and SLC1A2 in subregions of the dlPFC were significantly and marginally lower in subjects with MDD (n = 15) than in controls (n = 15) (p = 0.045 and 0.057, respectively). In addition, there was a positive correlation between these two molecules (n = 30, p < 0.05). Spearman's rank correlation analysis using all available datasets revealed that the expression levels of both GAD1 and SLC1A2 mRNAs were commonly correlated with the expression levels of several neuropathological markers in the dlPFC in all of the SNCID subjects (n = 60, p < 0.001). Most of these markers are known to be involved in the RAF/MEK/ERK signal transduction pathway. This exploratory study provides an initial step for future studies to investigate an association between the reductions in SLC1A2 and GAD1 mRNA expression and their relation to the attenuation of the RAF/MEK/ERK signaling pathway in the dlPFC in MDD. The integration of the existing archival data may shed light on one important aspect of the pathophysiology of MDD. © 2014 Springer-Verlag.

Hollins S.L.,University of Newcastle | Hollins S.L.,Schizophrenia Research Institute | Hollins S.L.,Hunter Medical Research Institute | Zavitsanou K.,University of New South Wales | And 6 more authors.
Translational Psychiatry | Year: 2014

A significant feature of the cortical neuropathology of schizophrenia is a disturbance in the biogenesis of short non-coding microRNA (miRNA) that regulate translation and stability of mRNA. While the biological origin of this phenomenon has not been defined, it is plausible that it relates to major environmental risk factors associated with the disorder such as exposure to maternal immune activation (MIA) and adolescent cannabis use. To explore this hypothesis, we administered the viral mimic poly I:C to pregnant rats and further exposed some of their maturing offsprings to daily injections of the synthetic cannabinoid HU210 for 14 days starting on postnatal day 35. Whole-genome miRNA expression analysis was then performed on the left and right hemispheres of the entorhinal cortex (EC), a region strongly associated with schizophrenia. Animals exposed to either treatment alone or in combination exhibited significant differences in the expression of miRNA in the left hemisphere, whereas the right hemisphere was less responsive. Hemisphere-associated differences in miRNA expression were greatest in the combined treatment and highly over-represented in a single imprinted locus on chromosome 6q32. This observation was significant as the syntenic 14q32 locus in humans encodes a large proportion of miRNAs differentially expressed in peripheral blood lymphocytes from patients with schizophrenia, suggesting that interaction of early and late environmental insults may affect miRNA expression, in a manner that is relevant to schizophrenia. © 2014 Macmillan Publishers Limited.

Catts V.S.,Schizophrenia Research Institute | Catts V.S.,Schizophrenia Research Laboratory | Catts V.S.,University of New South Wales | Weickert C.,Schizophrenia Research Institute | And 2 more authors.
PLoS ONE | Year: 2012

An increase in apoptotic events may underlie neuropathology in schizophrenia. By data-mining approaches, we identified significant expression changes in death receptor signaling pathways in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia, particularly implicating the Tumor Necrosis Factor Superfamily member 6 (FAS) receptor and the Tumor Necrosis Factor [ligand] Superfamily member 13 (TNFSF13) in schizophrenia. We sought to confirm and replicate in an independent tissue collection the noted mRNA changes with quantitative real-time RT-PCR. To test for regional and diagnostic specificity, tissue from orbital frontal cortex (OFC) was examined and a bipolar disorder group included. In schizophrenia, we confirmed and replicated significantly increased expression of TNFSF13 mRNA in the DLPFC. Also, a significantly larger proportion of subjects in the schizophrenia group had elevated FAS receptor expression in the DLPFC relative to unaffected controls. These changes were not observed in the bipolar disorder group. In the OFC, there were no significant differences in TNFSF13 or FAS receptor mRNA expression. Decreases in BH3 interacting domain death agonist (BID) mRNA transcript levels were found in the schizophrenia and bipolar disorder groups affecting both the DLPFC and the OFC. We tested if TNFSF13 mRNA expression correlated with neuronal mRNAs in the DLPFC, and found significant negative correlations with interneuron markers, parvalbumin and somatostatin, and a positive correlation with PPP1R9B (spinophilin), but not DLG4 (PSD-95). The expression of TNFSF13 mRNA in DLPFC correlated negatively with tissue pH, but decreasing pH in cultured cells did not cause increased TNFSF13 mRNA nor did exogenous TNFSF13 decrease pH. We concluded that increased TNFSF13 expression may be one of several cell-death cytokine abnormalities that contribute to the observed brain pathology in schizophrenia, and while increased TNFSF13 may be associated with lower brain pH, the change is not necessarily causally related to brain pH. © 2012 Catts, Shannon Weickert.

Lambe E.K.,University of Toronto | Fillman S.G.,Schizophrenia Research Institute | Fillman S.G.,Schizophrenia Research Laboratory | Fillman S.G.,University of New South Wales | And 4 more authors.
PLoS ONE | Year: 2011

Serotonin and its receptors (HTRs) play critical roles in brain development and in the regulation of cognition, mood, and anxiety. HTRs are highly expressed in human prefrontal cortex and exert control over prefrontal excitability. The serotonin system is a key treatment target for several psychiatric disorders; however, the effectiveness of these drugs varies according to age. Despite strong evidence for developmental changes in prefrontal Htrs of rodents, the developmental regulation of HTR expression in human prefrontal cortex has not been examined. Using postmortem human prefrontal brain tissue from across postnatal life, we investigated the expression of key serotonin receptors with distinct inhibitory (HTR1A, HTR5A) and excitatory (HTR2A, HTR2C, HTR4, HTR6) effects on cortical neurons, including two receptors which appear to be expressed to a greater degree in inhibitory interneurons of cerebral cortex (HTR2C, HTR6). We found distinct developmental patterns of expression for each of these six HTRs, with profound changes in expression occurring early in postnatal development and also into adulthood. However, a collective look at these HTRs in terms of their likely neurophysiological effects and major cellular localization leads to a model that suggests developmental changes in expression of these individual HTRs may not perturb an overall balance between inhibitory and excitatory effects. Examining and understanding the healthy balance is critical to appreciate how abnormal expression of an individual HTR may create a window of vulnerability for the emergence of psychiatric illness. © 2011 Lambe et al.

Dalton V.S.,Australian Nuclear Science and Technology Organization | Dalton V.S.,Schizophrenia Research Institute | Long L.E.,Schizophrenia Research Institute | Long L.E.,Schizophrenia Research Laboratory | And 6 more authors.
Neuropsychopharmacology | Year: 2011

A number of studies suggest a dysregulation of the endogenous cannabinoid system in schizophrenia (SCZ). In the present study, we examined cannabinoid CB 1 receptor (CB 1 R) binding and mRNA expression in the dorsolateral prefrontal cortex (DLPFC) (Brodmann's area 46) of SCZ patients and controls, post-mortem. Receptor density was investigated using autoradiography with the CB 1 R ligand 3H CP 55 940 and CB 1 R mRNA expression was measured using quantitative RT-PCR in a cohort of 16 patients with paranoid SCZ, 21 patients with non-paranoid SCZ and 37 controls matched for age, post-mortem interval and pH. All cases were obtained from the University of Sydney Tissue Resource Centre. Results were analyzed using one-way analysis of variance (ANOVA) and post hoc Bonferroni tests and with analysis of covariance (ANCOVA) to control for demographic factors that would potentially influence CB 1 R expression. There was a main effect of diagnosis on 3 H CP 55 940 binding quantified across all layers of the DLPFC (F(2,71)3.740, p0.029). Post hoc tests indicated that this main effect was due to patients with paranoid SCZ having 22% higher levels of CB 1 R binding compared with the control group. When ANCOVA was employed, this effect was strengthened (F(2,67)6.048, p0.004) with paranoid SCZ patients differing significantly from the control (p0.004) and from the non-paranoid group (p0.016). In contrast, no significant differences were observed in mRNA expression between the different disease subtypes and the control group. Our findings confirm the existence of a CB 1 R dysregulation in SCZ and underline the need for further investigation of the role of this receptor particularly in those diagnosed with paranoid SCZ. © 2011 American College of Neuropsychopharmacology. All rights reserved.

Fung S.J.,Schizophrenia Research Institute | Fung S.J.,Schizophrenia Research Laboratory | Fung S.J.,University of New South Wales | Fillman S.G.,Schizophrenia Research Institute | And 6 more authors.
Schizophrenia Research | Year: 2014

Schizophrenia and bipolar disorder are often viewed as distinct clinical disorders, however there is substantial overlap in their neuropathologies. While compromised cortical interneurons are implicated in both diseases, few studies have examined the relative contribution of the distinct interneuron populations to each psychotic disorder. We report reductions in somatostatin and vasoactive intestinal peptide mRNAs in prefrontal and orbitofrontal cortices in bipolar disorder (n. = 31) and schizophrenia (n. = 35) compared to controls (n. = 34) and increased calbindin mRNA in schizophrenia. We show, at the molecular level, shared deficits in interneuron markers in schizophrenia and bipolar disorder, and a unique interneuron marker increase in schizophrenia. © 2014 The Authors.

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