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David Cotter

Publications and source records attributed to David Cotter.

17 recordsLinked to original sources
PubMed2006

Hippocampal FGF-2 and FGFR1 mRNA expression in major depression, schizophrenia and bipolar disorder.

INTRODUCTION: FGF-2 is important for stem cell proliferation, neocortical development and adult neuronal survival and growth. Reduced frontal cortical FGF-2 expression is described in major depression and is attenuated by antidepressants. We determined the distribution of hippocampal FGF-2 and its receptor (FGFR1) mRNA in post-mortem brains of people who suffered from major depression, bipolar disorder and schizophrenia and those of controls. METHODS: FGF-2 and FGFR1 mRNA were measured within hippocampal CA1, CA4 regions and the dentate gyrus (DG), using in situ hybridization. Within hippocampal regions, cellular staining was compared between diagnostic groups, using repeated measures analysis of variance. RESULTS: The density of FGF-2 mRNA+ cells in CA4 was reduced in depression compared to controls. The percentage of FGFR1 mRNA+ cells was higher in depression (CA1 and CA4) and schizophrenia (CA4) than in controls. FGFR1 mRNA expression was higher in depression than in the other groups in CA1, CA4 and DG. Overall FGF-2 mRNA expression was higher in DG than in CA1 and CA4. CONCLUSIONS: We found raised measures of FGFR1 mRNA+ in major depression and, less so, in schizophrenia, along with reduced FGF-2 mRNA density in depression. Perturbations of FGF regulation could be relevant to the pathogenesis of both disorders as FGF-2 and FGFR1 are implicated in normal hippocampal synaptology, stem cell recruitment, and connectivity, and are modulated by corticosteroids.

Adult↗
PubMed2006

Proteomic analysis of the anterior cingulate cortex in the major psychiatric disorders: Evidence for disease-associated changes.

Abnormalities of the anterior cingulate cortex have previously been described in schizophrenia, major depressive disorder and bipolar disorder. In this study 2-DE was performed followed by mass spectrometric sequencing to identify disease-specific protein changes within the anterior cingulate cortex in these psychiatric disorders. The 2-DE system comprised IPGs 4-7 and 6-9 in the first, IEF dimension and SDS-PAGE in the second dimension. Resultant protein spots were compared between control and disease groups. Statistical analysis indicated that 35 spots were differentially expressed in one or more groups. Proteins comprising 26 of these spots were identified by mass spectroscopy. These represented 19 distinct proteins; aconitate hydratase, malate dehydrogenase, fructose bisphosphate aldolase A, ATP synthase, succinyl CoA ketoacid transferase, carbonic anhydrase, alpha- and beta-tubulin, dihydropyrimidinase-related protein-1 and -2, neuronal protein 25, trypsin precursor, glutamate dehydrogenase, glutamine synthetase, sorcin, vacuolar ATPase, creatine kinase, albumin and guanine nucleotide binding protein beta subunit. All but three of these proteins have previously been associated with the major psychiatric disorders. These findings provide support for the view that cytoskeletal and mitochondrial dysfunction are important components of the neuropathology of the major psychiatric disorders.

Adult↗
PubMed2006

Examination of 2-DE in the Human Proteome Organisation Brain Proteome Project pilot studies with the new RAIN gel matching technique.

The Human Proteome Organisation (HUPO) Brain Proteome Project (BPP) pilot studies have generated over 200 2-D gels from eight participating laboratories. This data includes 67 single-channel and 60 DIGE gels comparing 30 whole frozen C57/BL6 female mouse brains, ten each at embryonic day 16, postnatal day 7 (juvenile) and postnatal day 54-56 (adult); and ten single-channel and three DIGE gels comparing human epilepsy surgery of the temporal front lobe with a corresponding post-mortem specimen. The samples were generated centrally and distributed to the participating laboratories, but otherwise no restrictions were placed on sample preparation, running and staining protocols, nor on the 2-D gel analysis packages used. Spots were characterised by MS and the annotated gel images published on a ProteinScape web server. In order to examine the resultant differential expression and protein identifications, we have reprocessed a large subset of the gels using the newly developed RAIN (Robust Automated Image Normalisation) 2-D gel matching algorithm. Traditional approaches use symbolic representation of spots at the very early stages of the analysis, which introduces persistent errors due to inaccuracies in spot modelling and matching. With RAIN, image intensity distributions, rather than selected features, are used, where smooth geometric deformation and expression bias are modelled using multi-resolution image registration and bias-field correction. The method includes a new approach of volume-invariant warping which ensures the volume of protein expression under transformation is preserved. An image-based statistical expression analysis phase is then proposed, where small insignificant expression changes over one gel pair can be revealed when reinforced by the same consistent changes in others. Results of the proposed method as applied to the HUPO BPP data show significant intra-laboratory improvements in matching accuracy over a previous state-of-the-art technique, Multi-resolution Image Registration (MIR), and the commercial Progenesis PG240 package.

Algorithms↗
PubMed2006

Author retraction.

Explore the source record for details and available documents.

Retraction Notice↗
PubMed2005

Evidence for altered neuronal organisation within the planum temporale in major psychiatric disorders.

Reductions in neuronal size and glial cell density have been described in the frontal cortex in major psychiatric disorders. In this investigation, we performed a cytoarchitectural assessment within the planum temporale (PT), an auditory association region located within the superior temporal gyrus, using two-dimensional (2D) measures of cell size and density and spatial point pattern analysis. In sections of the PT from subjects with schizophrenia, bipolar disorder, major depressive disorder and controls (15 subjects per group), the laminar distribution and size of all neurons and glial cell nuclei was recorded. Spatial point pattern investigation demonstrated reduced neuronal clustering in bipolar disorder (p=0.033) and schizophrenia (p=0.027) compared with controls. Statistical analyses comparing each of the patient groups with the control group failed to identify differences in neuronal density between groups. Neuronal size was reduced in cortical layer 3 (p=0.02) and glial cell density reduced in cortical layer 6 (p=0.05) in bipolar disorder relative to controls but these findings did not remain significant after adjusting for six layer-wise comparisons. We propose that alterations in cortical cytoarchitecture within this region are subtle and involve reduced clustering of neurons, which may be due to altered neuronal organisation within cortical mini-columns or within cortical layers.

Adult↗
PubMed2005

Evidence for orbitofrontal pathology in bipolar disorder and major depression, but not in schizophrenia.

BACKGROUND: The orbitofrontal cortex is involved in the monitoring of reward and in judgement. Lesion studies and functional neuroimaging investigations implicate this region in affective disorders, and altered neuronal and glial cell composition have been observed in this region in subjects with major depressive disorder (MDD). AIMS: Stereologically based investigation of caudal orbitofrontal cortex (cOFC), in 60 postmortem brains from four groups of 14 subjects each with bipolar disorder (BPD), schizophrenia and MDD. METHODS: Glial cell and neuronal size and density were examined in all subjects using stereological probes such as the nucleator and the optical disector. RESULTS: We found statistical evidence for a neuronal size reduction in BPD in layer 1 (21%, p=0.007) and a trend for a reduction in layer 5 (20%, p=0.05). There was a significant interaction effect of brain hemisphere and group on neuronal size in layer 3 (p=0.001), with evidence for reduced layer 3 neuronal sizes in MDD (30%, p<0.001). We found no evidence for group differences in glial cell size nor for differences in glial or neuronal density. CONCLUSIONS: These findings provide preliminary evidence that neuronal size reduction in cOFC is a component of the pathology of BPD. Overall, the data implicate this cortical region in affective disorders, but provide no evidence for neuronal or glial pathology in this region in schizophrenia.

Adult↗
PubMed2004

Optimization of the first dimension for separation by two-dimensional gel electrophoresis of basic proteins from human brain tissue.

A major cause of poor resolution in the alkaline pH range of two-dimensional electrophoresis (2-DE) gels is unsatisfactory separation of basic proteins in the first dimension. We have compared methods for the separation of basic proteins in the isoelectric focusing dimension of human brain proteins. The combined use of anodic cup-loading and the hydroxyethyldisulphide containing solution (DeStreak) produced better resolution in both analytical and micropreparative protein loaded 2-DE gels than the other methods investigated.

Brain Chemistry↗
PubMed2004

Neurological soft signs and dermatoglyphic anomalies in twins with schizophrenia.

Schizophrenia is associated with altered neural development. We assessed neurological soft signs (NSS) and dermatoglyphic anomalies (total a-b ridge count (TABRC) and total finger ridge count) in 15 pairs of twins concordant and discordant for schizophrenia. Within-pair differences in both NSS and TABRC scores were significantly greater in discordant compared to concordant monozygotic pairs. There was no significant difference in NSS and TABRC scores between subjects with schizophrenia and their co-twins without the illness. However, monozygotic discordant twins with schizophrenia had higher ABRCs on their right hands compared to their co-twins without the illness. These findings suggest that an unidentified environmental event acting between weeks 6 and 15 of gestation affects the development of monozygotic twins who go on to develop schizophrenia but does not have a corresponding effect on their co-twins who do not develop the illness. The effect of such an event on dermatoglyphic profiles appears lateralised to the right hand in affected twins.

Adult↗
PubMed2004

The MADS-box transcription factor SrfA is required for actin cytoskeleton organization and spore coat stability during Dictyostelium sporulation.

The MADS-box transcription factor SrfA is involved in spore differentiation in Dictyostelium [Development 125 (1998) 3801]. Mutant spores show an altered morphology and loss of viability. A detailed structural analysis of mutant spores has been performed to gain insight into the specific aspects of spore differentiation in which SrfA is involved. Two main structural defects have been observed. One is the formation of high order actin structures, the so-called actin rods. SrfA mutant spores showed the initial stages of rod formation but no mature rods were found in older spores either in the nucleus or the cytoplasm. Moreover, phosphorylation of actin, that is believed to stabilize the actin rods, is strongly reduced in the mutant. The other defect observed was the formation of the spore coat. Young srfA- spores show basically normal trilaminar coat structures suggesting that release of prespore vesicles and basic assembly of the coat takes place in the absence of SrfA. However, the outer layer gets wavier as the spore ages and suffers a progressive degradation suggesting a late defect in the stability of the spore coat. Taken together, these results suggest that SrfA is involved in late events of spore maturation necessary for spore stability.

Actins↗
PubMed2004

Transcriptional transitions during Dictyostelium spore germination.

Many protozoa form spores in response to adversity; therefore, spore germination is a key process in their life cycle. Dictyostelium discoideum sporulates in response to starvation following a developmental program. Germination is characterized by two visible changes, spore swelling and the emergence of amoeba from the spore capsule. Several studies have indicated that an additional process termed spore activation is also required, but the physiological changes that characterize the three phases are largely uncharacterized. We used microarrays to monitor global transcriptional transitions as a surrogate measure of the physiological changes that occur during germination. Using two independent methods to induce germination, we identified changes in mRNA levels that characterized the germination process rather than changes that resulted from the induction method. We found that germination is characterized by three transitions. The first transition occurs during activation, while the spores appear dormant, the largest transition occurs when swelling begins, and the third transition occurs when emergence begins. These findings indicate that activation and swelling are not passive occurrences, such as dilution of inhibitors or spore rehydration, but are active processes that are accompanied by dramatic events in mRNA degradation and de novo transcription. These findings confirm and extend earlier reports that genes such as celA are regulated during spore germination. We also found by mutation analysis that the unconventional myosin gene myoI, which is induced during early germination, plays roles in the maintenance of dormancy and in spore swelling. This finding suggests that some of the observed transcriptional changes are required for spore germination.

Animals↗
PubMed2004

Cell density and cortical thickness in Heschl's gyrus in schizophrenia, major depression and bipolar disorder.

There is evidence that the superior temporal gyrus and Heschl's gyrus within it are implicated in schizophrenia. We investigated neuronal and glial cell density and cortical thickness within Heschl's gyrus, using the optical disector to estimate cell density within cortical layers 3 and 5 in tissue derived postmortem from people with diagnoses of major depressive disorder, schizophrenia and bipolar disorder, compared with normal controls (n=15 per group). No significant difference in neuronal or glial cell density or in cortical thickness was observed between the groups; our findings therefore provide no support for the presence of cellular pathology within Heschl's gyrus in schizophrenia.

Auditory Cortex↗
PubMed2003

Two-dimensional assessment of cytoarchitecture in the anterior cingulate cortex in major depressive disorder, bipolar disorder, and schizophrenia: evidence for decreased neuronal somal size and increased neuronal density.

BACKGROUND: Abnormalities of cortical neuronal organization and reductions in neuronal somal size have been reported in schizophrenia. The purpose of this investigation was to assess patterns of neuronal and glial distribution in the anterior cingulate cortex (ACC) in major depressive disorder (MDD), schizophrenia, bipolar disorder (BPD), and normal control subjects (15 subjects per group). METHODS: Estimates for neuronal somal and glial nuclear size and density were obtained. We employed two-dimensional morphometric analysis to examine the location of neurons and glia in a 1000-microm-wide strip of cortex. RESULTS: A decreased clustering of neurons was seen in BPD (p =.001). No other group differences were observed in the clustering of neurons, glia, or of neurons about glia. Neuronal somal size was reduced in layer 5 in schizophrenia (18%, p =.001), BPD (16%, p <.001), and MDD (9%, p =.01). Neuronal density was increased in layer 6 in BPD (63%, p =.004) and schizophrenia (61%, p =.006) and in layer 5 in MDD (24%, p =.018) and schizophrenia (33%, p =.003). CONCLUSIONS: The results of this study indicate that reduced neuronal somal size and increased neuronal density in cortical layers 5 and 6 of the ACC may be key features of schizophrenia, MDD, and BPD.

Adult↗
PubMed2002

An investigation of the Wnt-signalling pathway in the prefrontal cortex in schizophrenia, bipolar disorder and major depressive disorder.

The Wnt-signalling pathway has been implicated in a variety of processes including cortical development and plasticity. We have previously demonstrated a reduction in glycogen synthase kinase-3beta (GSK-3beta) levels in the prefrontal cortex in schizophrenia and aimed to further elucidate the abnormalities of the Wnt-signalling pathway in this and other psychiatric disorders. Immunoblotting was performed to quantify the levels of three members of the Wnt-signalling pathway, GSK-3beta, beta-catenin and dishevelled-2 (Dvl-2), in the prefrontal cortex in schizophrenia, bipolar disorder and major depressive disorder and in matched controls. We found no significant differences between the disease and control groups for any of the proteins studied, and therefore, cannot confirm our earlier findings of abnormalities of GSK-3beta in schizophrenia.

Adaptor Proteins, Signal Transducing↗
PubMed2002

The density and spatial distribution of GABAergic neurons, labelled using calcium binding proteins, in the anterior cingulate cortex in major depressive disorder, bipolar disorder, and schizophrenia.

BACKGROUND: There is strong evidence for the presence of a deficit in cortical gamma aminobutyric acid (GABA) neurotransmission in schizophrenia. In this investigation we have used the calcium binding proteins (CBPs) parvalbumin (PV), calretinin (CR), and calbindin-D28K (CB) as markers of these neuronal populations, and have characterized their pattern and density in schizophrenia, bipolar disorder (BPD), and major depressive disorder (MDD). METHODS: We examined the anterior cingulate cortex (ACC) in four groups of 15 brains each from subjects with schizophrenia, MDD, and BPD, and from control subjects. Using immunocytochemistry to identify these distinct neuronal populations, we quantified their areal density and spatial pattern organization. RESULTS: There were reductions in the density of CB-labeled neurons in layer 2 in schizophrenia (34%; p =.04) and BPD (33%; p =.05) compared with control subjects; however, after correction for multiple comparisons these findings no longer attained formal statistical significance. We observed no differences in the density of the neuronal populations labeled by CR or PV in any layer of the cortex in any disorder compared with control subjects. There was increased clustering among PV-labeled neurons in BPD compared with control subjects but no significant differences in the spatial organization of the other neuronal subpopulations in any disorder. CONCLUSIONS: The study provides some support for the presence of a deficit in GABAergic neurons in schizophrenia and shows that these changes are not specific to schizophrenia. The findings indicate that there may be a pathophysiological condition, shared by subjects with schizophrenia and BPD, which operates to selectively reduce the number or protein expression of CB-immunoreactive neurons.

Adult↗
PubMed2002

Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder.

Reductions in glial cell density and neuronal size have been described recently in major depressive disorder (MDD). Considering the important trophic influence of glia on neurons, we hypothesized that this glial cell deficit is more prominent close to neurons. In this investigation we have characterized neuronal and glia cytoarchitecture in prefrontal area 9 using spatial point pattern techniques and two-dimensional measures of cell size and density. In post-mortem brain tissue of subjects with MDD, schizophrenia, bipolar disorder (BPD), and normal controls (15 subjects per group), we examined the laminar location and size of all neurons and glial nuclei in a 500 microm wide strip of cortex extending from the pia to the grey-white matter border. In MDD, we observed reductions in glial cell density (30%; P = 0.007) in layer 5 and neuronal size (20%; P = 0.003) in layer 6. We also found that glial cell density (34%; P = 0.003) was reduced in layer 5 in schizophrenia, while neuronal size was reduced in layers 5 (14%) (P = 0.006) and 6 (18%; P = 0.007) in BPD. The spatial pattern investigation of neurons and glia demonstrated no alteration in the clustering of glia about neurons between control and patient groups. These findings confirm that glial cell loss and neuronal size reductions occur in the deeper cortical layers in MDD, but provide no support for the hypothesis that an altered spatial distribution of glia about neurons plays a role in the development of these changes.

Analysis of Variance↗
PubMed2002

Expression of Oct-6, a POU III domain transcription factor, in schizophrenia.

OBJECTIVE: Oct-6, a POU-III domain transcription factor, is expressed in embryonic stem cells and Schwann cells and in neuronal subpopulations during early mammalian development, but its relevance to disorders of cerebral development in humans is untested. This study evaluated the expression of Oct-6 in schizophrenia, a disorder that has been linked with neurodevelopmental abnormalities. METHOD: Immunohistochemistry was used to examine Oct-6 expression in the temporal lobe in postmortem tissue from 10 subjects with schizophrenia and 10 matched comparison subjects. Western blot analysis was used to study Oct-6 expression in the frontal and temporal cortex in tissue from an additional three schizophrenic and three matched comparison subjects and in the frontal lobe only in tissue from an additional 10 schizophrenic and 10 matched comparison subjects. RESULTS: Extensive Oct-6 immunoreactivity was present in the temporal lobe in all 10 schizophrenic subjects, while very little or no expression was found in the comparison subjects. In schizophrenic subjects, Oct-6 immunoreactivity was found in a subset of cells in the pyramidal cell layer of the hippocampus and in the granule cell layer of the dentate gyrus. Oct-6 staining was predominantly localized in the cytoplasm. Western blot analysis confirmed the presence of Oct-6 in the frontal and temporal cortex in schizophrenic subjects but not in comparison subjects. CONCLUSIONS: The presence of Oct-6 expression in the schizophrenic subjects but not in the comparison subjects suggests that Oct-6 may provide a marker for the neuropathology associated with schizophrenia. Further, it may provide a clue to the neurodevelopmental basis of the disease and could be a reliable means to examine the developmental brain abnormalities described in this disorder.

Adult↗