Dopaminergic regulation by D-aminoacid oxidase, an enzyme implicated in schizophrenia

Glutamate and dopamine are the brain chemicals (?neurotransmitters?) most involved in the severe mental illness called schizophrenia. One of the molecules that regulates glutamate signalling in the brain is D-amino acid oxidase (DAO). It does this by breaking down another molecule, D-serine, that is needed for glutamate signalling to work properly. Recent findings from our lab and others show that DAO and D-serine are affected in schizophrenia. In particular, there is too much DAO, and it is too active, in the brains of people with the illness. This leads to the theory that excessive DAO, and not enough D-serine, may be part of the ?glutamate problem? in schizophrenia and may contribute to some of the key symptoms and difficulties which patients with the illness experience. This project will examine a specific question about what DAO does in the brain and why it is relevant to schizophrenia. As noted above, dopamine as well as glutamate is involved in schizophrenia, yet we know little of the relationship between the two neurotransmitters. We recently found that DAO is, unexpectedly, present in the area of the brain that makes dopamine, suggesting that DAO may provide one of the links. We therefore want to study the effect of decreasing DAO activity on the function of dopamine in the brain, using a novel drug available to us. We will also map exactly where DAO is in relation to the dopamine nerve cells to help explain how and where it works. This project build upon our recent findings and current expertise, and is timely and important given the interest in DAO in the cause and the treatment of schizophrenia.

D-aminoacid oxidase (DAO) metabolises the NMDA receptor (NMDAR) co-agonist D-serine and other D-amino acids. NMDAR hypofunction is widely hypothesized to be a key pathophysiological feature of schizophrenia, especially its cognitive component. NMDAR involvement in schizophrenia is thought to be mediated primarily via effects upon dopamine (DA) transmission, and to arise, at least partly, from decreased D-serine availability. Various lines of evidence now implicate DAO directly in the NMDAR hypofunction: (1) DAO activity and expression are increased in schizophrenia; (2) DAO inactivation by genetic or pharmacological means has antipsychotic-like and cognitive-enhancing effects, and (3) there is some evidence for genetic association with schizophrenia and related phenotypes for DAO and for the putative DAO-activator gene G72. For these reasons, DAO - along with other molecules involved in NMDAR co-agonism - is now a therapeutic target under investigation to treat schizophrenia, as well as some other disorders. However, critical questions about DAO in the brain and in schizophrenia remain unknown, notably, the impact of DAO on DA function and how this is mediated. Our recent data show that DAO is unexpectedly present and active in the mibdrain, and other findings show that NMDAR modulation impacts on DA function. Moreover, DAO may have particular relevance for the mesocortical DA pathway, centrally implicated in the cognitive dysfunction of schizophrenia. The current project takes advantage of our existing expertise and our unique access to a novel DAO inhibitor to address these issues. It has three main components. (1) We will study the effect of systemic and local (ventral tegmental area, VTA) DAO inhibition on DA release in medial prefrontal cortex and nucleus accumbens. (2) Using electrophysiology, juxtacellular labelling and antidromic stimulation we will study the effect of systemic and local DAO inhibition upon firing of mesocortical and mesolimbic VTA neurons.(3) We will map the cellular distribution of DAO in the VTA, to establish its localisation within DA as opposed to non-DA cells. The studies will together allow a detailed, translational approach that will clarify the relationship between DAO and DA function, providing information that is directly relevant to the therapeutic candidacy of DAO inhibitors as well as to the hypothesis of its involvement in the schizophrenia disease process.