The expression and function of glutamatergic susceptibility genes in schizophrenia

Lead Research Organisation: University of Oxford
Department Name: Experimental Psychology

Abstract

A number of genes that may affect people’s risk of getting schizophrenia have recently been identified. Although the evidence is still incomplete, it has been suggested that they share in common an effect on how a key chemical transmitter, called glutamate, functions in the brain. We want to investigate this question further, to help understand the mechanisms by which the genes work. To do this, we will study in detail where exactly the genes are expressed in the brain, what the differences are in people with the illness, and between people with different variants (‘polymorphisms’) of each gene. We will also study, in various experimental models, the consequences of manipulating the genes in a way that mimics the alterations seen in the illness. Overall, our objective is to discover important clues about the genetic and biological abnormalities that underlie schizophrenia, and which may help in the development of better drug treatments.

Technical Summary

A number of susceptibility genes for schizophrenia have recently been identified. There are two notable features of the findings. First, most of the genes are thought to have their primary actions upon glutamatergic synaptic transmission, consistent with prior evidence of glutamatergic and synaptic dysfunction in schizophrenia affecting NMDAR transmission. Second, the genetic variants that are associated with the disease are virtually all non-coding; as such, they probably exert their effects via altered gene expression. This combination of discoveries leads to the hypothesis that abnormalities of the glutamatergic synapse are a core pathophysiological mechanism for schizophrenia, arising from alterations in some facet of expression of the genes. This project, which is in essence a targeted functional genomics study, has three components. (1) We will study five of the genes (DAOA, DAAO, GRM3, CNAalpha, ZDHHC8), in detail in adult human and developing brain, to identify the location and ontogeny of their mRNA and protein expression, using a range of methods. (2) We will establish whether the expression of the genes is affected by schizophrenia or by genetic polymorphisms, using large series of human brain tissue. We predict that these components will reveal expression profiles supportive of a genetically-mediated impairment of NMDAR signalling in schizophrenia. (3) The final component comprises experimental studies to address complementary issues which are impractical in human brain (e.g. ultrastructural immunolocalisation, embryological studies), and in order to examine the causes and consequences, in vitro, of up- and down-regulation of expression of the genes. In total, the project is translational, revealing not only the differences in expression of these genes in schizophrenia, but also using experimental systems to inform the human work and to identify the molecular basis and functional correlates of the altered expression. Identification of a convergent, genetically influenced, biochemical pathway would be a major advance for the understanding of schizophrenia, and a basis for targeted pharmacotherapeutic interventions to modify the disease process rather than merely suppress its symptoms. This project will contribute significantly to this ambitious but now realistic goal.

Publications

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Eastwood SL (2008) Decreased mRNA expression of netrin-G1 and netrin-G2 in the temporal lobe in schizophrenia and bipolar disorder. in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

 
Description Senior Founding Member of the University of Oxford Cortex Club
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact The Cortex Club connects researchers at the University of Oxford with world-leading neuroscientists through a unique educational forum dealing with cutting-edge topics and significant challenges in neuroscience. Our events range from small intense debates with up-and-coming scientists to large discussion sessions led by internationally prominent speakers, followed by the opportunity to ask them questions over drinks.
URL http://cortexclub.com
 
Description Strategic Grant
Amount £391,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2008 
End 03/2011
 
Description Translational studies of group II metabotropic glutamate receptors (mGluR2, mGluR3) and their role in schizophrenia 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution Generated idea, and leading on experimental work.
Collaborator Contribution Facilitated other interactions with, and support from, GSK
Impact Helped lead to an MRC pilot industry award between ourselves and GSK, funded in October 2008.
Start Year 2008
 
Description Interview to the OX Magazine on Brain Awareness Week 2017 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact From the 10th March the Museum of Natural History are opening an exhibition and series of events on the mysteries of neurological development - Brain Diaries. I was approached by the OX Magazine to give an interview and discuss the highlights of this exhibition and also my own research. This was produced for the general public in Oxfordshire.
The interview can be accessed on: http://oxhc.co.uk/Brain-Diaries-In-conversation-with-Professor-Zoltan-Molnar.asp
Year(s) Of Engagement Activity 2016
URL http://oxhc.co.uk/Brain-Diaries-In-conversation-with-Professor-Zoltan-Molnar.asp
 
Description School visit 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Primary Audience Schools
Results and Impact Gave lectures and answered questions about schizophrenia, its genes, and its overall causation.

Interest from students in psychology and neuroscience as a career.
Year(s) Of Engagement Activity 2008,2009
 
Description School visit - by Sharon Eastwood 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Primary Audience Schools
Results and Impact Talked in school about nature of science and specifics of own research.

Not known
Year(s) Of Engagement Activity 2009