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

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.

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.