ORCID Profile
0000-0002-6719-1126
Current Organisations
Royal College of Psychiatrists
,
University of Oxford
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Publisher: Wiley
Date: 11-2003
Publisher: Wiley
Date: 2006
DOI: 10.1002/HIPO.20194
Abstract: 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 hippoc us. In this study, the integral synaptic vesicle protein synaptophysin, measured immunoautoradiographically, was used as an index of synaptic terminal abundance in the hippoc al formation of 37 subjects from 5 weeks to 86 yr old, ided into 4 age groups (10 infants, 15 adolescents/young adults, 6 adults, and 6 elderly). In all hippoc al 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 hippoc us. We also measured synaptophysin mRNA in the human subjects and found no age-related changes, except in parahippoc al 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 hippoc al development. In so far as synaptophysin abundance reflects synaptic density, the findings support an increase in hippoc al and parahippoc al 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 hippoc al formation.
Publisher: Wiley
Date: 25-05-2005
DOI: 10.1111/J.1365-2990.2005.00662.X
Abstract: Depressive symptoms in the elderly are common and disabling and constitute a risk factor for the development of Alzheimer's disease (AD). One hypothesis worth exploring is that depression in the elderly is related to development of AD pathology at subcortical sites before such pathology develops in the hippoc us and neocortex. We describe here an autopsy study of the locus ceruleus (LC) and raphe nuclei (RN) in nine subjects with depression and 18 age and sex matched controls that were included in a community-based study of cognitive function and ageing (MRC-CFAS). We found no relationship between depression and (1) mean counts of serotonergic or total RN neuronal profiles (2) noradrenergic or total LC neuronal profiles (3) counts of neurofibrillary tangles in these nuclei, or (4) size of neurones in the RN. Nor were these parameters related to age or sex of the subjects. We conclude that depression in the elderly is unlikely to be related to RN or LC neurone counts or RN cell size or to AD-type pathology in these nuclei. However, because of the small numbers of cases studied and our inability to carry out a full stereological study because of tissue limitations the findings are preliminary.
Publisher: Elsevier BV
Date: 2017
Publisher: Elsevier BV
Date: 2010
Publisher: Oxford University Press (OUP)
Date: 06-10-2016
DOI: 10.5665/SLEEP.5342
Publisher: Elsevier BV
Date: 2004
Publisher: Proceedings of the National Academy of Sciences
Date: 25-04-2006
Abstract: Genetic variation in neuregulin 1 ( NRG1 ) is associated with schizophrenia. The disease-associated SNPs are noncoding, and their functional implications remain unknown. We hypothesized that differential expression of the NRG1 gene explains its association to the disease. We examined four of the disease-associated SNPs that make up the original risk haplotype in the 5′ upstream region of the gene for their effects on mRNA abundance of NRG1 types I–IV in human postmortem hippoc us. Diagnostic comparisons revealed a 34% increase in type I mRNA in schizophrenia and an interaction of diagnosis and genotype (SNP8NRG221132) on this transcript. Of potentially greater interest, a single SNP within the risk haplotype (SNP8NRG243177) and a 22-kb block of this core haplotype are associated with mRNA expression for the novel type IV isoform in patients and controls. Bioinformatic promoter analyses indicate that both SNPs lead to a gain/loss of putative binding sites for three transcription factors, serum response factor, myelin transcription factor-1, and High Mobility Group Box Protein-1. These data implicate variation in isoform expression as a molecular mechanism for the genetic association of NRG1 with schizophrenia.
Publisher: Springer Science and Business Media LLC
Date: 09-07-2008
DOI: 10.1038/NPP.2008.106
Publisher: Oxford University Press (OUP)
Date: 11-07-2006
Abstract: The prefrontal cortex (PFC) dopamine system, which is critical for modulating PFC function, undergoes remodeling until at least young adulthood in primates. Catechol-o-methyltransferase (COMT) alters extracellular dopamine levels in PFC, and its gene contains a functional polymorphism (Val(158)Met) that has been associated with variation in PFC function. We examined COMT enzyme activity and protein immunoreactivity in the PFC during human postnatal development. Protein was extracted from PFC of normal in iduals from 6 age groups: neonates (1-4 months), infants (5-11 months), teens (14-18 years), young adults (20-24 years), adults (31-43 years), and aged in iduals (68-86 years n = 5-8 per group). There was a significant 2-fold increase in COMT enzyme activity from neonate to adulthood, paralleled by increases in COMT protein immunoreactivity. Furthermore, COMT protein immunoreactivity was related to Val(158)Met genotype, as has been previously demonstrated. The significant increase in COMT activity from neonate to adulthood complements previous findings of protracted postnatal changes in the PFC dopamine system and may reflect an increasing importance of COMT for PFC dopamine regulation during maturation.
Publisher: Elsevier BV
Date: 2016
Publisher: Wiley
Date: 09-2003
DOI: 10.1046/J.1460-9568.2003.02850.X
Abstract: The N-methyl-d-aspartate receptor plays a critical role in the formation and maintenance of synapses during brain development. In the rodent, changes in subunit expression and assembly of the heteromeric receptor complex accompany these maturational processes. However, little is known about N-methyl-d-aspartate receptor subunit expression during human brain development. We used in situ hybridization to examine the distribution and relative abundance of NR1, NR2A and NR2B subunit messenger ribonucleic acids in the hippoc al formation and adjacent cortex of 34 human subjects at five stages of life (neonate, infant, adolescent, young adult and adult). At all ages, the three messenger ribonucleic acids were expressed in all subfields, predominantly by pyramidal neurons, granule cells and polymorphic hilar cells. However, their abundance varied across ontogeny. Levels of NR1 messenger ribonucleic acid in CA4, CA3 and CA2 subfields were significantly lower in the neonate than all other age groups. In the dentate gyrus, subiculum and parahippoc al gyrus, NR2B messenger ribonucleic acid levels were higher in the neonate than in older age groups. NR2A messenger ribonucleic acid levels remained constant, leading to an age-related increase in NR2A/2B transcript ratio. We conclude that N-methyl-d-aspartate receptor subunit messenger ribonucleic acids are differentially expressed during postnatal development of the human hippoc us, with a pattern similar but not identical to that seen in the rodent. Changes in subunit composition may thus contribute to maturational differences in human hippoc al N-methyl-d-aspartate receptor function, and to their role in the pathophysiology of schizophrenia and other neurodevelopmental disorders.
Publisher: Cold Spring Harbor Laboratory
Date: 03-08-2020
DOI: 10.1101/2020.08.02.232785
Abstract: Accurately quantifying gene and isoform expression changes is essential to understanding cell functions, differentiation and disease. Therefore, a crucial requirement of RNA sequencing is identifying differential expression. The recent development of long-read direct RNA (dRNA) sequencing has the potential to overcome many limitations of short and long-read sequencing methods that require RNA fragmentation, cDNA synthesis or PCR. dRNA sequences native RNA and can encompass an entire RNA in a single read. However, its ability to identify differential gene and isoform expression in complex organisms is poorly characterised. Using a mixture of synthetic controls and human SH-SY5Y cell differentiation into neuron-like cells, we show that dRNA sequencing accurately quantifies RNA expression and identifies differential expression of genes and isoforms. We generated ∼4 million dRNA reads with a median length of 991 nt. On average, reads covered 74% of SH-SY5Y transcripts and 29% were full-length. Measurement of expression and fold changes between synthetic control RNAs confirmed accurate quantification of genes and isoforms. Differential expression of 231 genes, 291 isoforms, plus 27 isoform switches were detected between undifferentiated and differentiated SH-SY5Y cells and s les clustered by differentiation state at the gene and isoform level. Genes upregulated in neuron-like cells were associated with neurogenesis. We further identified ,000 expressed transcripts including thousands of novel splice isoforms and transcriptional units. Our results establish the ability of dRNA sequencing to identify biologically relevant differences in gene and isoform expression and perform the key capabilities of expression profiling methodologies.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Paul Harrison.