The role of catechol-o-methyltransferase (COMT) in hippocampal function

Lead Research Organisation: University of Oxford
Department Name: Psychiatry

Abstract

Anxiety disorders and psychiatric disorders affecting memory (including schizophrenia) are common, and often recurrent and severe. Existing treatments are unsatisfactory, largely because the conditions are poorly understood. A part of the brain, the hippocampus, is critically involved in memory and anxiety, and in these disorders. Hippocampal function is influenced by the chemical tranmsitter, dopamine. Catechol-0-methyl transferase (COMT) is a gene that contributes to memory and anxiety, probably because it breaks down dopamine. However, it is not known what COMT does in the hippocampus. We want to investigate this question, as we predict that it contributes to dopamine s actions in the hippocampus, and to its malfunction in the psychiatric disorders mentioned. Also, drugs that block COMT are being tested as treatments for these disorders, and so our research will help in showing their effects on the brain, and so aid the development of more effective and safer drugs of this kind.

Technical Summary

The enzyme catechol-o-methyltransferase (COMT) degrades catecholamines. It is implicated in a range of brain phenotypes, including working memory, emotional processing, anxiety, and psychosis. These effects probably occur via its role in dopamine metabolism, and are modulated by a common functional polymorphism (Val158Met) that influences COMT activity. Most work to date has focused on the prefrontal cortex, but there are strong indications that COMT is also important in the hippocampus, wherein the roles and mechanisms of COMT may differ. The aim of this project is to investigate COMT in hippocampal function, with particular regard to the involvement of COMT in the pathophysiology of psychiatric disorders and the use of COMT inhibitors in their treatment. To achieve this aim, we will decrease COMT activity in rodents, both genetically (using a mouse that expresses a humanized COMT gene and pharmacologically (using a brain-penetrant COMT inhibitor, tolcapone) and study the consequences upon key parameters of hippocampal function: catecholamine metabolism, synaptic transmission and plasticity, hippocampal-dependent behaviours, and dopaminergic innervation and receptor expression. In addition, human hippocampal COMT expression will be determined in those with schizophrenia and mood disorder, and in relation to COMT genotype. The work will take into account the evidence for sex differences in COMT, for ventrodorsal differences in hippocampal function and its dopaminergic regulation, and for the possibility that noradrenergic as well as dopaminergic transmission may be affected. In total, the project is comprehensive, multifaceted, and translational. Given the diverse evidence implicating COMT in the pathogenesis of several major psychiatric disorders, and the emerging use of COMT inhibitors as therapeutic agents, the results will be of direct and immediate clinical significance.

Publications

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Barkus C (2016) Genotype-Dependent Effects of COMT Inhibition on Cognitive Function in a Highly Specific, Novel Mouse Model of Altered COMT Activity. in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

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Barkus C (2013) Genetic mouse models of depression. in Current topics in behavioral neurosciences

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Harrison PJ (2008) Catechol-O-methyltransferase (COMT): a gene contributing to sex differences in brain function, and to sexual dimorphism in the predisposition to psychiatric disorders. in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

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Tunbridge EM (2008) Polymorphisms in the catechol-O-methyltransferase (COMT) gene influence plasma total homocysteine levels. in American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics

 
Description Royal Society University Fellowship (for Dr EM Tunbridge)
Amount £500,000 (GBP)
Organisation The Royal Society 
Sector Academic/University
Country United Kingdom
Start 01/2010 
End 12/2014
 
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 BA Festival of Science 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Primary Audience Policymakers/politicians
Results and Impact Presented poster at House of Commons

Not known
Year(s) Of Engagement Activity 2008
 
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 Science Oxford 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Primary Audience Public/other audiences
Results and Impact Talk given by Elizabeth Tunbridge (co-applicant)

Not known
Year(s) Of Engagement Activity 2008