Brian Dean

Brian Dean
The Florey Institute of Neuroscience and Mental Health · Molecualr Psychiatry Laboratory

HND AppBiol, MSc, PhD, FSBiol, CBiol.

About

362
Publications
26,388
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11,985
Citations
Introduction
Skills and Expertise
Additional affiliations
June 2014 - present
The Florey Institute of Neuroscience and Mental Health
Position
  • Laboratory Head
June 1987 - December 2013
Mental Health Research Institute
Mental Health Research Institute
Position
  • Principal Investigator

Publications

Publications (362)
Preprint
In psychiatric disorders, common and rare genetic variants cause widespread dysfunction of cells and their interactions, especially in the prefrontal cortex, giving rise to psychiatric symptoms. To better understand these processes, we traced the effects of common and rare genetics, and cumulative disease risk scores, to their molecular footprints...
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Postmortem and neuroimaging studies show low levels of cortical muscarinic M1 receptors (CHRM1) in patients with schizophrenia which is significant because CHRM signalling has been shown to change levels of gene expression and cortical gene expression is altered in schizophrenia. We decided to identify CHRM1-mediated changes in cortical gene expres...
Article
Background : Brain-derived neurotrophic factor (BDNF) antisense RNA (BDNF-AS) was identified as naturally conserved non-coding antisense RNA that suppresses the transcription of BDNF. Methods : We measured the expression of BDNF mRNA and BDNF-AS mRNA in iPSC and NSC from bipolar disorder (BD) patients and healthy control subjects, and postmortem b...
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Background We have previously reported reduced expression of the cholinergic autoreceptor CHRM2 in Brodmann's Area (BA) 24 of the anterior cingulate cortex from subjects with major depressive disorder (MDD) and bipolar disorder (BD), consistent with a hypercholinergic state. This led us to investigate whether levels of the high affinity nicotinic a...
Article
Estrogens, via estrogen-mediated changes in CNS function, have been suggested to be beneficial in the treatment of several psychiatric disorders. Few studies have used transcriptomic technologies to determine the effect of estrogen on gene expression in the CNS. Thus, we aimed to examine the impact of ovariectomy (the removal of all ovarian hormone...
Article
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 a...
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Structural changes in the corpus callosum have been reported in schizophrenia; however, the underlying molecular mechanism remains unclear. As the corpus callosum is high in lipid content, we analyzed the lipid contents of the corpora callosa from 15 patients with schizophrenia and 15 age- and sex-matched controls using liquid chromatography couple...
Article
It has been suggested the study of sub-groups within the syndrome of schizophrenia will assist in elucidating the complex pathophysiology of the syndrome. Hence, we have studied a number of cholinergic markers in the cortex from a sub-group of subjects with schizophrenia that have a marked decrease in levels of muscarinic M1 receptors (MRDS). The d...
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The disturbed integrity of myelin and white matter, along with dysregulation of the lipid metabolism, may be involved in schizophrenia pathophysiology. Considering the crucial role of sphingolipids in neurodevelopment, particularly in oligodendrocyte differentiation and myelination, we examined the role of sphingolipid dynamics in the pathophysiolo...
Article
The finding that the drug KarXT, a formulation of xanomeline and tropsium which targets muscarinic receptors, has given a positive result in reducing the positive and negative symptoms of schizophrenia in a phase II trial suggests targeting muscarinic receptors is a new approach to treating the disorder. This review will detail the synergistic inte...
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Ovarian hormones, such as estrogens and progesterone, are known to exert beneficial effects on cognition and some psychiatric disorders. The basis of these effects is not fully understood, but may involve altered cholinergic neurotransmission. This study aimed to investigate how a lack of ovarian hormones would impact muscarinic receptor-induced de...
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Having reported associations between catechol-O-methyltransferase (COMT) genotypes at SNPs rs4818 and rs4680 with levels of soluble COMT (S-COMT) in human dorsolateral prefrontal cortex (DLPFC), we postulated that changes in the levels of cortical S-COMT could impact on behavioural abilities associated with COMT genotype through S-COMT-mediated cha...
Article
Excitatory amino acid transporter (EAAT)1 and EAAT2 mediate glutamatergic neurotransmission and prevent excitotoxicity through binding and transportation of glutamate into glia. These EAATs may be regulated by metabotropic glutamate receptor 5 (mGluR5), which is also expressed by glia. Whilst we have data from an Affymetrix™ Human Exon 1.0 ST Array...
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Mice with the C3H background show greater behavioral propensity for schizophrenia, including lower prepulse inhibition (PPI), than C57BL/6 (B6) mice. To characterize as-yet-unknown pathophysiologies of schizophrenia, we undertook proteomics analysis of the brain in these strains, and detected elevated levels of Mpst, a hydrogen sulfide (H2 S)/polys...
Article
A large body of work implicates cytokines and their related pathways in the pathophysiologies of mood disorders. Much of the data on the role of cytokines in major depression and bipolar disorder suggest that pathways regulated by tumor necrosis factor (TNF)‐α make a significant contribution to their pathophysiologies. In the present review, we con...
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Background: Pre-clinical and some human data suggests allosteric modulation of the muscarinic M1 receptor (CHRM1) is a promising approach for the treatment of schizophrenia. However, it is suggested there is a sub-group of subjects with schizophrenia who have profound loss of cortical CHRM1 (MRDS). This raises the possibility that some subjects wi...
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Background Mood disorders likely occur in someone with a genetic predisposition who encounters a deleterious environmental factor leading to dysregulated physiological processes due to genetic mutations and epigenetic mechanisms altering gene expression. To gain data to support this hypothesis, we measured levels of gene expression in three cortica...
Article
Objectives: The objective of this study was to determine whether a breakdown in proteins regulating cortical iron homeostasis could be involved in the pathophysiology of mood disorders. Methods: Levels of select proteins responsible for cortical iron transport were quantitated by Western blotting of Brodmann’s (BA) areas 6 and 10 from patients with...
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Objective: ATPase Type 13A4 (ATP13A4) is a cation-transporting, P5-type ATPase that has been implicated in neurodevelopmental disorders. Our recent microarray study reported a significant increase in ATP13A4 mRNA levels in Brodmann’s Area (BA) 9 in subjects with schizophrenia compared to controls. Following this discovery we have sought to determin...
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Schizophrenia (Sz) probably occurs after genetically susceptible individuals encounter a deleterious environmental factor that triggers epigenetic mechanisms to change CNS gene expression. To determine if omnibus changes in CNS gene expression are present in Sz, we compared mRNA levels in the frontal pole (Brodmann's area (BA) 10), the dorsolateral...
Article
Levels of a reference protein must be the same as a proportion of total protein in all tissues and, in the study of human diseases, cannot vary with factors such as age, gender or disease pathophysiology. It is increasingly apparent that there may be few, if any, proteins that display the characteristics of a reference protein within the human cent...
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Sex differences are a prominent feature of the pathophysiology of psychiatric disorders, such as major depressive disorder which affects women at a higher incidence than men. Research suggests that the most potent endogenous estrogen, 17β‐estradiol, may have therapeutic potential in treating depression. However, preclinical studies have produced mi...
Article
Catechol-O-methyltransferase (COMT) is an enzyme that catalyses the O-methylation, and thereby the inactivation, of catechol-containing molecules. In humans, it has been suggested that COMT modulates cognitive ability, possibly by regulating degradation of dopamine in the prefrontal cortex. Hence, it is significant that two COMT SNPs, rs4680 (c.472...
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Background: Results of neuroimaging and postmortem studies suggest that people with schizophrenia may have lower levels of muscarinic M1 receptors (CHRM1) in the cortex, but not in the hippocampus or thalamus. Here, we use a novel immunohistochemical approach to better understand the likely cause of these low receptor levels. Methods: We determi...
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Objectives: To create a gene expression signature (GES) to represent the biological effects of a combination of known drugs for bipolar disorder (BD) on cultured human neuronal cells (NT2-N) and rat brains, which also has evidence of differential expression in individuals with BD. To use the GES to identify new drugs for BD using Connectivity Map (...
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Glutamate is the predominant excitatory neurotransmitter in the human brain and it has been shown that prolonged activation of the glutamatergic system leads to nerve damage and cell death. Following release from the pre-synaptic neuron and synaptic transmission, glutamate is either taken up into the pre-synaptic neuron or neighbouring glia by tran...
Article
Background: Results of neuroimaging and postmortem studies suggest that people with schizophrenia may have lower levels of muscarinic M1 receptors (CHRM1) in the cortex, but not in the hippocampus or thalamus. Here, we use a novel immunohistochemical approach to better understand the likely cause of these low receptor levels. Methods: We determi...
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Full-text available
Schizophrenia is associated with diverse changes in the brain’s transcriptome and proteome. Underlying these changes is the complex dysregulation of gene expression and protein production that varies both spatially across brain regions and temporally with the progression of the illness. The growing body of literature showing changes in non-coding R...
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Background Evidence from postmortem CNS studies and a neuroimaging study suggest that, compared to controls, there are low levels of muscarinic receptors in a number of CNS regions from subjects with schizophrenia. Current data suggests the muscarinic M1 receptor is lower in the cortex of subjects with schizophrenia but other muscarinic receptors m...
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Background Antipsychotic drugs plus aspirin (acetylsalicylic acid), which targets prostaglandin-endoperoxide synthase 1 (PTGS1: COX1), improved therapeutic outcomes when treating schizophrenia. Our microarray data showed higher levels of PTGS1 mRNA in the dorsolateral prefrontal cortex from subjects with schizophrenia of long duration of illness, s...
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Our previous study demonstrated that phospholipase C beta 1 mRNA was down-regulated in Brodmann’s area 46 from subjects with schizophrenia. However, phospholipase C beta 1 protein has also been shown to be lower in Brodmann’s area 8 and 9 from teenage suicide subjects, creating a potential confound in interpreting the findings in schizophrenia due...
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It has been suggest that drugs specifically targeting muscarinic receptors will be useful in treating Alzheimer’s disease. We decided to determine if the response to such drugs may be altered, because of changes in the levels of muscarinic receptors in the CNS from subjects with the disorder. We used in situ radioligand binding with autoradiography...
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Background: We tested the hypothesis that changes in gene expression in the dorsolateral prefrontal cortex (DLPFC) from 2 sub-groups of subjects with schizophrenia, one with a marked deficit in muscarinic M1 receptors (MRDS), would identify different biochemical pathways that would be affected by their aetiologies. Methods: We measured levels of mR...
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Parkinson’s disease (PD) is a devastating disorder, affecting approximately 2% of people aged 60 and above. It is marked by progressive neurodegeneration that has long been known to impact dopaminergic cells and circuits, but more recently the acetylcholine system has also been implicated in the complex aetiology and symptomatology of the disease....
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Background: Studies investigating the relationship between n-3 polyunsaturated fatty acid (PUFA) levels and psychiatric disorders have thus far focused mainly on analyzing gray matter, rather than white matter, in the postmortem brain. In this study, we investigated whether PUFA levels showed abnormalities in the corpus callosum, the largest area...
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Studies using central nervous system tissue obtained postmortem suggest pathways involved in energy and metabolism contribute to the pathophysiology of schizophrenia; neuroimaging studies suggesting glucose metabolism is particularly affected in the striatum. To gain information on the status of pathways involved in glucose metabolism in the striat...
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We tested the hypothesis that, compared with subjects with no history of psychiatric illness (controls), changes in gene expression in the dorsolateral prefrontal cortex from two subgroups of subjects with schizophrenia, one with a marked deficit in muscarinic M1 receptors (muscarinic receptor-deficit schizophrenia (MRDS)), would identify different...
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Given the complexity and heterogeneity of the genomic architecture underlying schizophrenia, molecular analyses of these patients with defined and large effect-size genomic defects could provide valuable clues. We established human-induced pluripotent stem cells from two schizophrenia patients with the 22q11.2 deletion (two cell lines from each sub...
Article
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 es...
Article
The muscarinic M1 receptor plays a significant role in cognition, probably by modulating information processing in key regions such as the hippocampus. To understand how the muscarinic M1 receptor achieves these functions in the hippocampus, it is critical to know the distribution of the receptor within this complex brain region. To date, there are...
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Background: It is common practice, when using quantitative real time polymerase chain reaction (qPCR), to normalise levels of mRNA to reference gene mRNA which, by definition, should not vary between tissue, with any disease aetiology or after drug treatments. The complexity of human CNS means it unlikely that any gene could fulfil these criteria....
Article
The Melbourne Psychiatric Brain Bank came into existence 25years ago. This review focusses on lines of research that have used tissue from the Brain Bank over periods of time. Hence there is a discussion on the significance of changes in levels of serotonin 2A receptors in the cortex of patients with schizophrenia and the relevance of such changes...
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Identifying biomarkers that can be used as diagnostics or predictors of treatment response (theranostics) in people with schizophrenia (Sz) will be an important step towards being able to provide personalized treatment. Findings from the studies in brain tissue have not yet been translated into biomarkers that are practical in clinical use because...
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Our expression microarray studies showed messenger RNA (mRNA) for solute carrier family 39 (zinc transporter), member 12 (SLC39A12) was higher in dorsolateral prefrontal cortex from subjects with schizophrenia (Sz) in comparison with controls. To better understand the significance of these data we ascertained whether SLC39A12 mRNA was altered in a...
Article
Catechol-O-methyltransferase (COMT) genotype has been associated with varying levels of cognitive functioning and an altered risk of schizophrenia. COMT regulates the breakdown of catecholamines, particularly dopamine, which is thought critical in maintaining cognitive function and the aetiology of schizophrenia. This hypothesis gained support from...
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Background: Cognitive deficits are amongst the most socially debilitating and least effectively treated symptoms of schizophrenia. The cholinergic system is a promising target for the design of novel drugs that can more effectively treat these symptoms. Methods: We review the literature supporting the dysfunction of the cholinergic system in sch...
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Based on our previous finding of a seven-miRNA (hsa-miR-34a, miR-449a, miR-564, miR-432, miR-548d, miR-572 and miR-652) signature as a potential biomarker for schizophrenia, this study aimed to examine if hospitalization could affect expressions of these miRNAs. We compared their expression levels between acute state and partial remission state in...