Common polymorphisms in dopamine-related genes combine to produce a ‘schizophrenia-like' prefrontal hypoactivity

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Individual changes in dopamine-related genes influence prefrontal activity during cognitive-affective processes; however, the extent to which common genetic variations combine to influence prefrontal activity is unknown. We assessed catechol- O-methyltransferase (COMT) Val108/158Met (rs4680) and dopamine D2 receptor (DRD2) G-T (rs2283265) single nucleotide polymorphisms and functional magnetic resonance imaging during an emotional response inhibition test in 43 healthy adults and 27 people with schizophrenia to determine the extent to which COMT Val108/158Met and DRD2 G-T polymorphisms combine to influence prefrontal response to cognitive-affective challenges. We found an increased number of cognitive-deficit risk alleles in these two dopamine-regulating genes predict reduced prefrontal activation during response inhibition in healthy adults, mimicking schizophrenia-like prefrontal hypoactivity. Our study provides evidence that functionally related genes can combine to produce a disease-like endophenotype.

Related collections

Most cited references 34

Record: found
Abstract: found
Article: not found

The positive and negative syndrome scale (PANSS) for schizophrenia.

L Opler, Jennifer Kay, Paul Opler … (1986)

The variable results of positive-negative research with schizophrenics underscore the importance of well-characterized, standardized measurement techniques. We report on the development and initial standardization of the Positive and Negative Syndrome Scale (PANSS) for typological and dimensional assessment. Based on two established psychiatric rating systems, the 30-item PANSS was conceived as an operationalized, drug-sensitive instrument that provides balanced representation of positive and negative symptoms and gauges their relationship to one another and to global psychopathology. It thus constitutes four scales measuring positive and negative syndromes, their differential, and general severity of illness. Study of 101 schizophrenics found the four scales to be normally distributed and supported their reliability and stability. Positive and negative scores were inversely correlated once their common association with general psychopathology was extracted, suggesting that they represent mutually exclusive constructs. Review of five studies involving the PANSS provided evidence of its criterion-related validity with antecedent, genealogical, and concurrent measures, its predictive validity, its drug sensitivity, and its utility for both typological and dimensional assessment.

0 comments Cited 1803 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain.

Jingshan Chen, Barbara K Lipska, Nader Halim … (2004)

Catechol-O-methyltransferase (COMT) is a key enzyme in the elimination of dopamine in the prefrontal cortex of the human brain. Genetic variation in the COMT gene (MIM 116790) has been associated with altered prefrontal cortex function and higher risk for schizophrenia, but the specific alleles and their functional implications have been controversial. We analyzed the effects of several single-nucleotide polymorphisms (SNPs) within COMT on mRNA expression levels (using reverse-transcriptase polymerase chain reaction analysis), protein levels (using Western blot analysis), and enzyme activity (using catechol methylation) in a large sample (n = 108) of postmortem human prefrontal cortex tissue, which predominantly expresses the -membrane-bound isoform. A common coding SNP, Val158Met (rs4680), significantly affected protein abundance and enzyme activity but not mRNA expression levels, suggesting that differences in protein integrity account for the difference in enzyme activity between alleles. A SNP in intron 1 (rs737865) and a SNP in the 3' flanking region (rs165599)--both of which have been reported to contribute to allelic expression differences and to be associated with schizophrenia as part of a haplotype with Val--had no effect on mRNA expression levels, protein immunoreactivity, or enzyme activity. In lymphocytes from 47 subjects, we confirmed a similar effect on enzyme activity in samples with the Val/Met genotype but no effect in samples with the intron 1 or 3' SNPs. Separate analyses revealed that the subject's sex, as well as the presence of a SNP in the P2 promoter region (rs2097603), had small effects on COMT enzyme activity. Using site-directed mutagenesis of mouse COMT cDNA, followed by in vitro translation, we found that the conversion of Leu at the homologous position into Met or Val progressively and significantly diminished enzyme activity. Thus, although we cannot exclude a more complex genetic basis for functional effects of COMT, Val is a predominant factor that determines higher COMT activity in the prefrontal cortex, which presumably leads to lower synaptic dopamine levels and relatively deleterious prefrontal function.

0 comments Cited 352 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

The principal features and mechanisms of dopamine modulation in the prefrontal cortex.

Jeremy Seamans, Charles Yang (2004)

Mesocortical [corrected] dopamine (DA) inputs to the prefrontal cortex (PFC) play a critical role in normal cognitive process and neuropsychiatic pathologies. This DA input regulates aspects of working memory function, planning and attention, and its dysfunctions may underlie positive and negative symptoms and cognitive deficits associated with schizophrenia. Despite intense research, there is still a lack of clear understanding of the basic principles of actions of DA in the PFC. In recent years, there has been considerable efforts by many groups to understand the cellular mechanisms of DA modulation of PFC neurons. However, the results of these efforts often lead to contradictions and controversies. One principal feature of DA that is agreed by most researchers is that DA is a neuromodulator and is clearly not an excitatory or inhibitory neurotransmitter. The present article aims to identify certain principles of DA mechanisms by drawing on published, as well as unpublished data from PFC and other CNS sites to shed light on aspects of DA neuromodulation and address some of the existing controversies. Eighteen key features about DA modulation have been identified. These points directly impact on the end result of DA neuromodulation, and in some cases explain why DA does not yield identical effects under all experimental conditions. It will become apparent that DA's actions in PFC are subtle and depend on a variety of factors that can no longer be ignored. Some of these key factors include distinct bell-shaped dose-response profiles of postsynaptic DA effects, different postsynaptic responses that are contingent on the duration of DA receptor stimulation, prolonged duration effects, bidirectional effects following activation of D1 and D2 classes of receptors and membrane potential state and history dependence of subsequent DA actions. It is hoped that these factors will be borne in mind in future research and as a result a more consistent picture of DA neuromodulation in the PFC will emerge. Based on these factors, a theory is proposed for DA's action in PFC. This theory suggests that DA acts to expand or contract the breadth of information held in working memory buffers in PFC networks.

0 comments Cited 311 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): Transl Psychiatry

Journal ID (iso-abbrev): Transl Psychiatry

Title: Translational Psychiatry

Publisher: Nature Publishing Group

ISSN (Electronic): 2158-3188

Publication date (Print): February 2014

Publication date (Electronic): 04 February 2014

Publication date PMC-release: 1 February 2014

Volume: 4

Issue: 2

Page: e356

Affiliations

[1 ]School of Psychiatry, University of New South Wales , Sydney, NSW, Australia

[2 ]Schizophrenia Research Lab, Neuroscience Research Australia , Sydney, NSW, Australia

[3 ]Schizophrenia Research Institute , Darlinghurst, NSW, Australia

[4 ]School of Psychology, Australian Catholic University , Strathfield, NSW, Australia

[5 ]School of Medical Sciences, University of New South Wales , Sydney, NSW, Australia

Author notes

[* ]Neuroscience Research Australia, Barker Street , Randwick, NSW 2031, Australia. E-mail: t.weickert@ 123456unsw.edu.au

Author information

P R Schofield http://orcid.org/0000-0003-2967-9662

Article

Publisher Item ID: tp2013125

DOI: 10.1038/tp.2013.125

PMC ID: 3944629

PubMed ID: 24495967

SO-VID: 60494069-e9a2-4513-932f-36bd87c1dd07

License:

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

History

Date received : 26 July 2013

Date revision received : 06 November 2013

Date accepted : 07 December 2013

Comments

Comment on this article

scite_

Cited by 6

See all cited by

Common polymorphisms in dopamine-related genes combine to produce a ‘schizophrenia-like' prefrontal hypoactivity

Read this article at

Abstract

Related collections

European Yearbook of the History of Psychology

Most cited references 34

The positive and negative syndrome scale (PANSS) for schizophrenia.

Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain.

The principal features and mechanisms of dopamine modulation in the prefrontal cortex.

Author and article information

Journal

Affiliations

Author notes

Author information

Article

History

Categories

Comments

Comment on this article

Similar content 134

Cited by 6