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Sharon L Eastwood

Publications and source records attributed to Sharon L Eastwood.

11 recordsLinked to original sources
PubMed2014

Expression of ZNF804A in human brain and alterations in schizophrenia, bipolar disorder, and major depressive disorder: a novel transcript fetally regulated by the psychosis risk variant rs1344706.

IMPORTANCE: The single-nucleotide polymorphism rs1344706 in the zinc finger protein 804A gene (ZNF804A) shows genome-wide association with schizophrenia and bipolar disorder. Little is known regarding the expression of ZNF804A and the functionality of rs1344706. OBJECTIVES: To characterize ZNF804A expression in human brain and to investigate how it changes across the life span and how it is affected by rs1344706, schizophrenia, bipolar disorder, and major depressive disorder. DESIGN, SETTING, AND PARTICIPANTS: Molecular and immunochemical methods were used to study ZNF804A messenger RNA (mRNA) and ZNF804A protein, respectively. ZNF804A transcripts were investigated using next-generation sequencing and polymerase chain reaction-based methods, and ZNF804A protein was investigated using Western blots and immunohistochemistry. Samples of dorsolateral prefrontal cortex and inferior parietal lobe tissue were interrogated from 697 participants between 14 weeks' gestational age and age 85 years, including patients with schizophrenia, bipolar disorder, or major depressive disorder. MAIN OUTCOMES AND MEASURES: Quantitative measurements of ZNF804A mRNA and immunoreactivity, and the effect of diagnosis and rs1344706 genotype. RESULTS: ZNF804A was expressed across the life span, with highest expression prenatally. An abundant and developmentally regulated truncated ZNF804A transcript was identified, missing exons 1 and 2 (ZNF804AE3E4) and predicted to encode a protein lacking the zinc finger domain. rs1344706 influenced expression of ZNF804AE3E4 mRNA in fetal brain (P&#x2009;=&#x2009;.02). In contrast, full-length ZNF804A showed no association with genotype (P&#x2009;>&#x2009;.05). ZNF804AE3E4 mRNA expression was decreased in patients with schizophrenia (P&#x2009;=&#x2009;.006) and increased in those with major depressive disorder (P&#x2009;<&#x2009;.001), and there was a genotype-by-diagnosis interaction in bipolar disorder (P&#x2009;=&#x2009;.002). ZNF804A immunoreactivity was detected in fetal and adult human cerebral cortex. It was localized primarily to pyramidal neurons, with cytoplasmic as well as dendritic and nuclear staining. No differences in ZNF804A-immunoreactive neurons were seen in schizophrenia or related to rs1344706 (P&#x2009;>&#x2009;.05). CONCLUSIONS AND RELEVANCE: rs1344706 influences the expression of ZNF804AE3E4, a novel splice variant. The effect is limited to fetal brain and to this isoform. It may be part of the mechanism by which allelic variation in ZNF804A affects risk of psychosis. ZNF804A is translated in human brain, where its functions may extend beyond its predicted role as a transcription factor.

Adolescent↗
PubMed2006

Altered expression of synaptic protein mRNAs in STOP (MAP6) mutant mice.

Stable tubule-only polypeptide (STOP) proteins are a family of microtubule associated proteins (MAPs) important in microtubule stabilization. Data indicating a role for microtubules in synaptic function has come from studies of the STOP null mouse, which exhibits synaptic deficits, in association with behavioural changes that are alleviated by antipsychotic treatment. These findings suggested that STOP mutant mice may be useful in studies of synaptic function, and could be especially relevant to schizophrenia, postulated to be a disorder of the synapse. Moreover, a genetic association between STOP and schizophrenia has been reported. This study aimed to further characterize synaptic alterations in STOP null and heterozygous mice. Using in situ hybridization histochemistry, the mRNA expression of three pre-synaptic (synaptophysin; growth associated protein-43 (GAP-43); vesicular glutamate transporter-1 (VGlut1)) and two post-synaptic (spinophilin; MAP2) proteins, was quantified in female STOP null (n = 7), heterozygous (n = 5) and wild type (n = 6) mice. For STOP null and heterozygous mice, synaptophysin, VGlut1, GAP-43 and spinophilin mRNAs were decreased in the hippocampus, whilst in addition in the null mice, synaptophysin, VGlut1 and spinophilin mRNAs were decreased in the cerebellum. Alterations in synaptic protein mRNA expression were also detected in the frontal and occipital cortex. MAP2 mRNA expression was unchanged in all brain regions. The profile of mRNA changes is broadly similar to that observed in schizophrenia. Together the data provide supporting evidence for a role for microtubules in synaptic function, and suggest that STOP, or other microtubule proteins, may contribute to the synaptic pathology of schizophrenia.

Animals↗
PubMed2006

Synaptophysin protein and mRNA expression in the human hippocampal formation from birth to old age.

In the human neocortex, progressive synaptogenesis in early postnatal life is followed by a decline in synaptic density, then stability from adolescence until middle age. No comparable data are available in the hippocampus. In this study, the integral synaptic vesicle protein synaptophysin, measured immunoautoradiographically, was used as an index of synaptic terminal abundance in the hippocampal formation of 37 subjects from 5 weeks to 86 yr old, divided into 4 age groups (10 infants, 15 adolescents/young adults, 6 adults, and 6 elderly). In all hippocampal subfields, synaptophysin was lowest in infancy, but did not differ significantly between the older age groups, except in dentate gyrus (DG) where the rise was delayed until adulthood. A similar developmental profile was found in the rat hippocampus. We also measured synaptophysin mRNA in the human subjects and found no age-related changes, except in parahippocampal gyrus wherein the mRNA declined from infancy to adolescence, and again in old age. The synaptophysin protein data demonstrate a significant presynaptic component to human postnatal hippocampal development. In so far as synaptophysin abundance reflects synaptic density, the findings support an increase in hippocampal and parahippocampal synapse formation during early childhood, but provide no evidence for adolescent synaptic pruning. The mRNA data indicate that the maturational increases in synaptophysin protein are either translational rather than transcriptional in origin, or else are secondary to mRNA increases in neurons, the cell bodies of which lie outside the hippocampal formation.

Adolescent↗
PubMed2006

Cellular basis of reduced cortical reelin expression in schizophrenia.

OBJECTIVE: The authors' goals were to establish the cellular origin of the reduced cortical reelin expression that occurs in schizophrenia and to relate it to markers of synaptic pathology. METHOD: In situ hybridization was used to quantify reelin mRNA in the hippocampal formation and dorsolateral prefrontal cortex of brains from 13 subjects with schizophrenia and 12 subjects without schizophrenia. Results were correlated with the expression of three synaptic protein genes in the dentate gyrus. RESULTS: Reelin mRNA was expressed by layer I neurons, interneurons, and interstitial white matter neurons. In subjects with schizophrenia, less reelin mRNA was expressed by interstitial white matter neurons in the hippocampal formation and by all three cell types in the prefrontal cortex. Reelin and synaptic protein expression correlated positively. CONCLUSIONS: Interstitial white matter neurons, presumed remnants of the cortical subplate, contribute to the reduction in reelin mRNA in schizophrenia. Down-regulation of reelin expression may in turn contribute to the synaptic pathology of the disorder.

Cell Adhesion Molecules, Neuronal↗
PubMed2006

Anomalies of asymmetry of pyramidal cell density and structure in dorsolateral prefrontal cortex in schizophrenia.

BACKGROUND: Studies suggest that neuronal density in left dorsolateral prefrontal cortex is increased in schizophrenia. AIMS: To replicate these findings and extend them to both hemispheres. METHOD: Neuronal density, size and shape were estimated in the prefrontal cortex (Brodmann area 9) of the left and right hemispheres of brains taken post-mortem from 10 people with schizophrenia and 10 without mental illness (6 men, 4 women in both groups). RESULTS: Overall neuronal density (individually corrected for shrinkage) did not differ between the groups. In the control brains, density was generally greater in the left than the right hemisphere, the reverse was seen in the schizophrenia brains; this loss or reversal of asymmetry was most significant in cortical layer 3. Pyramidal neurons in this cell layer were significantly larger on the left and more spherical in shape than on the right side in control brains, but size and shape did not differ between the two sides in schizophrenia. Non-pyramidal and glial cell densities were unchanged. CONCLUSIONS: We failed to find an increase in neuronal density, but found evidence at a cellular level of loss or reversal of asymmetry, consistent with the hypothesis of a primary change in the relative development of areas of heteromodal association cortex in the two hemispheres.

Aged↗
PubMed2005

Decreased hippocampal expression of the susceptibility gene PPP3CC and other calcineurin subunits in schizophrenia.

BACKGROUND: Calcineurin (CaN) is a phosphatase involved in synaptic plasticity. A haplotype of the PPP3CC gene, which encodes the gamma isoform of the catalytic subunit (CaN A), has been associated with schizophrenia. However, the distribution of CaN A gamma is not established, nor whether its expression changes in schizophrenia. METHODS: CaN A expression was analyzed in the hippocampal formation of 13 patients with schizophrenia and 12 controls. All three isoforms were examined, using in situ hybridization histochemistry, RT-PCR, and laser-assisted microdissection. CaN A protein was assessed using ELISA and immunohistochemistry. CaN A mRNAs were also measured in rats treated with haloperidol or chlorpromazine. RESULTS: CaN was prominent in excitatory neurons. CaN A alpha and A beta isoforms were abundant in all subfields, but CaN A gamma was not reliably detected in CA1. CaN A protein, and all three mRNAs, were decreased in schizophrenia. The mRNA reductions were present in all subfields measured, except CA1. CaN A mRNAs were unaltered in the antipsychotic-treated rats. CONCLUSIONS: Decreased CaN expression extends the evidence for aberrant hippocampal synaptic plasticity in schizophrenia, which particularly affects glutamatergic transmission, and which leaves CA1 relatively unaffected. Reduced expression of PPP3CC may underlie its genetic involvement in the disorder.

Aged↗
PubMed2005

Differential expression of calcineurin A subunit mRNA isoforms during rat hippocampal and cerebellar development.

Calcineurin (protein phosphatase 2B) is a calcium-dependent serine-threonine phosphatase. It has diverse roles and is centrally involved in synaptic plasticity. The catalytic A subunit of calcineurin has three isoforms, alpha, beta and gamma. Their expression and ontogeny in the brain has not been systematically investigated; such data become important with a report that PPP3CC, the gene encoding calcineurin Agamma, is a susceptibility gene for schizophrenia, and the finding that its expression is decreased in the disorder. We used in situ hybridization histochemistry to measure the relative transcript abundance of calcineurin Agamma and the other catalytic isoforms, Aalpha and Abeta, during development of the Sprague-Dawley rat hippocampus and cerebellum. All three isoforms are present in both regions at all time points [embryonic day 19 (E19) to postnatal day 42 (P42)] and undergo developmental regulation, but differ in their ontogenic profile. Calcineurin Aalpha and Abeta mRNAs increased from E19 through to adulthood, whereas Agamma mRNA was most highly expressed during early developmental stages. Calcineurin Aalpha and Abeta mRNAs positively correlated with synaptophysin mRNA (a synaptic marker), whilst Agamma mRNA was either unrelated to, or negatively correlated, with this transcript. These data confirm that all three calcineurin A subunits are expressed in the rodent brain, and indicate that calcineurin Agamma may have different roles than Aalpha and Abeta. The data also suggest a potential importance of calcineurin Agamma in neurodevelopment, and in the genetically influenced neurodevelopmental disturbance that is thought to underlie schizophrenia.

Age Factors↗
PubMed2004

Laser-assisted microdissection: methods for the molecular analysis of psychiatric disorders at a cellular resolution.

Gene expression arrays and proteomics together provide a great opportunity to reveal the molecular pathophysiology of psychiatric disorders; however, their potential will not be realized unless due attention is paid to the cellular heterogeneity of the brain and the likely differential neuropathological involvement of specific neuronal and glial cell types. Hence, methods are needed which can procure homogeneous populations of cells as a source of messenger RNA, protein, or DNA. Laser-assisted microdissection techniques provide such a tool. Here we briefly discuss the principles, applications, and limitations of laser-assisted microdissection in psychiatric research.

Animals↗
PubMed2004

The synaptic pathology of schizophrenia: is aberrant neurodevelopment and plasticity to blame?

Synaptic pathology is a feature of the brain in schizophrenia, denoted by alterations in the expression of synaptic proteins. In the absence of data indicative of neurodegenerative processes, the neuropathological features of schizophrenia suggest that the major pathogenic process in the disorder is one of aberrant development. Molecular evidence in support of a neurodevelopmental origin of schizophrenia has come from studies examining the expression of key developmental genes. However, as many of these genes are also involved in synaptic plasticity, their altered expression in schizophrenia also suggests that the disorder may be one of aberrant synaptic plasticity. The aim of this review is to explore whether aberrant development and synaptic plasticity may underlie the synaptic pathology of schizophrenia. It does this in two ways. First, studies in schizophrenia of the expression of two synaptic genes important in synaptic remodeling and plasticity are reviewed, changes in which may be indicative of aberrant synaptic plasticity in the disorder. Second, the possible relationship between the expression of genes involved in development and plasticity with that of presynaptic proteins is examined. Such a relationship, in combination with their altered expression in schizophrenia, may indicate whether developmental and plasticity-related processes may contribute to the synaptic pathology of the disorder. A brief discussion on the possible origins of the synaptic pathology of schizophrenia, and possible future studies, concludes the review.

Animals↗
PubMed2003

Glutamate receptors and transporters in the hippocampus in schizophrenia.

Postmortem studies, using various methods and directed at several molecular targets, have provided increasing evidence that glutamatergic neurotransmission is affected in schizophrenia. The bulk of the data are in the hippocampus, wherein there is reduced expression of one or more subunits for all three ionotropic receptors (NMDA, AMPA, and kainate). Presynaptic glutamatergic markers, notably the vesicular glutamate transporter VGLUT1, may also be decreased in schizophrenia, especially in older subjects. CA1 appears less affected than other subfields, and the decrements may be greater in the left than in the right hippocampus. The recently described susceptibility genes for schizophrenia all act upon glutamatergic synaptic transmission, which may, therefore, be part of the core pathophysiology of the disorder.

Amino Acid Transport System X-AG↗