Maree Webster

Publications (104) View all

• Source

  Available from: Leonora E Long

  Article: Developmental trajectory of the endocannabinoid system in human dorsolateral prefrontal cortex.

  Leonora E Long, Jonna Lind, Maree Webster, Cynthia Shannon Weickert
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  ABSTRACT: Endocannabinoids provide control over cortical neurotransmission. We investigated the developmental expression of key genes in the endocannabinoid system across human postnatal life and determined whether they correspond to the development of markers for inhibitory interneurons, which shape cortical development. We used microarray with qPCR validation and in situ hybridisation to quantify mRNA for the central endocannabinoid receptor CB1R, endocannabinoid synthetic enzymes (DAGLα for 2-arachidonylglycerol [2-AG] and NAPE-PLD for anandamide), and inactivating enzymes (MGL and ABHD6 for 2-AG and FAAH for anandamide) in human dorsolateral prefrontal cortex (39 days - 49 years). CB1R mRNA decreases until adulthood, particularly in layer II, after peaking between neonates and toddlers. DAGLα mRNA expression is lowest in early life and adulthood, peaking between school age and young adulthood. MGL expression declines after peaking in infancy, while ABHD6 increases from neonatal age. NAPE-PLD and FAAH expression increase steadily after infancy, peaking in adulthood. Stronger endocannabinoid regulation of presynaptic neurotransmission in both supragranular and infragranular cortical layers as indexed through higher CB1R mRNA may occur within the first few years of human life. After adolescence, higher mRNA levels of the anandamide synthetic and inactivating enzymes NAPE-PLD and FAAH suggest that a late developmental switch may occur where anandamide is more strongly regulated after adolescence than earlier in life. Thus, expression of key genes in the endocannabinoid system changes with maturation of cortical function.
  BMC Neuroscience 07/2012; 13:87. · 3.04 Impact Factor
• Article: Neuropathology markers and pathways associated with molecular targets for antipsychotic drugs in postmortem brain tissues: exploration of drug targets through the Stanley Neuropathology Integrative Database.

  Sanghyeon Kim, Katerina Zavitsanou, George Gurguis, Maree J Webster
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  ABSTRACT: The atypical antipsychotics bind multiple receptor targets, including dopamine D2 receptors (DRD2), 5-HT2 receptors (HTR2A), α-2 adrenergic receptors (ADRA2A), and muscarinic receptors (CHRM1/4). Deficits in antipsychotic targets, their associated pathways, and the causal relationships between the various targets were explored using the Stanley Neuropathology Consortium Integrative Database (SNCID; http://sncid.stanleyresearch.org) and the Network Edge Orienting (NEO) software. There were brain region-specific deficits in the level of the antipsychotic targets, and the level of each target correlated with the mRNA level of the neurotrophic factor BDNF. While myelination was a common process correlated with both DRD2 mRNA levels and ADRA2A activity in the frontal cortex, metabolic processes were specifically correlated with DRD2 mRNA. Immune and inflammatory responses and apoptosis pathways were correlated with group II metabotropic glutamate receptors (GRM2), which are a target for the development of the next-generation antipsychotics. The NEO analysis revealed that HTR2A and GRM2 are likely to regulate BDNF levels in the hippocampus and frontal cortex, respectively, whereas DRD2 and ADRA2A activity are likely to be regulated by BDNF in the frontal cortex. BDNF may play an important role in mechanisms of action of the current antipsychotics and the next-generation antipsychotics that target GRM2. However, this data-mining approach indicates that the next-generation antipsychotics are likely to work through pathways that are distinct from those through which the current antipsychotics work. Exploratory analyses such as these may initiate future hypothesis-driven studies to reveal the mechanisms of action underlying the efficacy and side-effects of the antipsychotics.
  European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 02/2012; 22(10):683-94. · 3.68 Impact Factor
• Article: Expression of NPAS3 in the Human Cortex and Evidence of Its Posttranscriptional Regulation by miR-17 During Development, With Implications for Schizophrenia.

  Jenny Wong, Carlotta E Duncan, Natalie J Beveridge, Maree J Webster, Murray J Cairns, Cynthia Shannon Weickert
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  ABSTRACT: NPAS3 is a developmentally important transcription factor that has been associated with psychiatric illness. Our aim is to better define the regulation of NPAS3 mRNA (messenger RNA) levels during normal human prefrontal cortical development and in schizophrenia. Utilizing postmortem tissue from 134 human brains, we assessed: 60 normal brains ranging in age from birth to adulthood, 37 chronic individuals with schizophrenia, and 37 matched controls. mRNA and microRNA (miRNA) expressions were measured by microarray and quantitative real-time PCR. Protein expression was measured by Western blotting. During human postnatal cortical development (neonate to adult), we found decreased NPAS3 mRNA yet increased NPAS3 protein expression, suggesting the involvement of posttranscriptional regulation. Through screening, we identified one NPAS-targeted miRNA (miR-17) that changed in a pattern consistent with the developmental regulation of NPAS3. Using luciferase reporter assays, we assessed the impact of miR-17 on NPAS3 translation and demonstrated that miR-17 alters NPAS3 biosynthesis by binding to the NPAS3 3'untranslated region (UTR). In schizophrenia prefrontal cortex, we found significant elevations in miR-17 expression. While NPAS3 mRNA was unaltered, reduced NPAS3 protein expression was detected in a subpopulation of people with schizophrenia. The reciprocal expression of NPAS3 mRNA and protein during postnatal development mediated by a schizophrenia-associated change in miR-17 suggests that there is complex control over NPAS3 synthesis in the human prefrontal cortex and that if NPAS3 is dysregulated in schizophrenia, it is not evident by large changes in NPAS3 expression. Further studies into how changes in NPAS3 or its miRNA regulator may influence the development of schizophrenia are warranted.
  Schizophrenia Bulletin 01/2012; · 8.80 Impact Factor
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  Available from: Maree Webster

  Article: Glucocorticoid receptor 1B and 1C mRNA transcript alterations in schizophrenia and bipolar disorder, and their possible regulation by GR gene variants.

  Duncan Sinclair, Janice M Fullerton, Maree J Webster, Cynthia Shannon Weickert
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  ABSTRACT: Abnormal patterns of HPA axis activation, under basal conditions and in response to stress, are found in individuals with schizophrenia and bipolar disorder. Altered glucocorticoid receptor (GR) mRNA and protein expression in the dorsolateral prefrontal cortex (DLPFC) in psychiatric illness have also been reported, but the cause of these abnormalities is not known. We quantified expression of GR mRNA transcript variants which employ different 5' promoters, in 35 schizophrenia cases, 31 bipolar disorder cases and 34 controls. We also explored whether sequence variation within the NR3C1 (GR) gene is related to GR mRNA variant expression. Total GR mRNA was decreased in the DLPFC in schizophrenia cases relative to controls (15.1%, p<0.0005) and also relative to bipolar disorder cases (8.9%, p<0.05). GR-1B mRNA was decreased in schizophrenia cases relative to controls (20.2%, p<0.05), while GR-1C mRNA was decreased in both schizophrenia and bipolar disorder cases relative to controls (16.1% and 17.2% respectively, both p<0.005). A dose-dependent effect of rs10052957 genotype on GR-1B mRNA expression was observed, where CC homozygotes displayed 18.4% lower expression than TC heterozygotes (p<0.05), and 31.8% lower expression than TT homozygotes (p<0.005). Similarly, a relationship between rs6190 (R23K) genotype and GR-1C expression was seen, with 24.8% lower expression in GG homozygotes than GA heterozygotes (p<0.01). We also observed an effect of rs41423247 (Bcl1) SNP on expression of 67 kDa GRα isoform, the most abundant GRα isoform in the DLPFC. These findings suggest possible roles for the GR-1B and GR-1C promoter regions in mediating GR gene expression changes in psychotic illness, and highlight the potential importance of sequence variation within the NR3C1 gene in modulating GR mRNA expression in the DLPFC.
  PLoS ONE 01/2012; 7(3):e31720. · 4.09 Impact Factor
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  Available from: Maree Webster

  Article: Genome-wide DNA methylation scan in major depressive disorder.

  Sarven Sabunciyan, Martin J Aryee, Rafael A Irizarry, Michael Rongione, Maree J Webster, Walter E Kaufman, Peter Murakami, Andree Lessard, Robert H Yolken, Andrew P Feinberg, James B Potash
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  ABSTRACT: While genome-wide association studies are ongoing to identify sequence variation influencing susceptibility to major depressive disorder (MDD), epigenetic marks, such as DNA methylation, which can be influenced by environment, might also play a role. Here we present the first genome-wide DNA methylation (DNAm) scan in MDD. We compared 39 postmortem frontal cortex MDD samples to 26 controls. DNA was hybridized to our Comprehensive High-throughput Arrays for Relative Methylation (CHARM) platform, covering 3.5 million CpGs. CHARM identified 224 candidate regions with DNAm differences >10%. These regions are highly enriched for neuronal growth and development genes. Ten of 17 regions for which validation was attempted showed true DNAm differences; the greatest were in PRIMA1, with 12-15% increased DNAm in MDD (p = 0.0002-0.0003), and a concomitant decrease in gene expression. These results must be considered pilot data, however, as we could only test replication in a small number of additional brain samples (n = 16), which showed no significant difference in PRIMA1. Because PRIMA1 anchors acetylcholinesterase in neuronal membranes, decreased expression could result in decreased enzyme function and increased cholinergic transmission, consistent with a role in MDD. We observed decreased immunoreactivity for acetylcholinesterase in MDD brain with increased PRIMA1 DNAm, non-significant at p = 0.08.While we cannot draw firm conclusions about PRIMA1 DNAm in MDD, the involvement of neuronal development genes across the set showing differential methylation suggests a role for epigenetics in the illness. Further studies using limbic system brain regions might shed additional light on this role.
  PLoS ONE 01/2012; 7(4):e34451. · 4.09 Impact Factor