D-amino acid oxidase: a potential therapeutic target for schizophrenia

D-amino acid oxidase (DAO) has been implicated as a risk gene and potential therapeutic target for schizophrenia. Previous studies have shown that abnormalities in dopaminergic neural circuits are implicated in the disorder but there is little evidence of how DAO affects the dopamine pathway and therefore how DAO based therapies may work.

DAO is an enzyme that breaks down D-amino acids. In the brain its main substrate is D-serine a co-agonist of NMDA receptors, whose activity has a downstream effect on the dopaminergic system.

A group from the University of Oxford, including lead author Dr Judith Schweimer, have measured the electrophysiological properties of dopaminergic (DA) neurons and non-DA neurons of the ventral tegmental area (VTA) in DAO-/- knockout mice to investigate this issue. They compared these properties with their DAO+/- heterozygous and DAO+/+ (wild-type) littermates to assess the effects of DAO on the DA neurons.

Extracellular electrophysiological recordings were made with glass microelectrodes lowered onto the VTA using Scientifica's single-axis IVM micromanipulator. These recordings showed that DA neurons of DAO-/- mice had greater numbers of burst-firing DA neurons in the VTA and non-DA neurons had a lower firing rate than wild-type and heterozygous DAO mice.

One way of explaining these results is that in DAO-/- mice the elevated levels of D-serine lead to greater NMDA receptor function. These NMDA receptors may be directly on the DA neurons. However, the difference could also be caused by a number of indirect routes. Further studies will be needed to elucidate the actual mechanism.

DAO inhibitors are already being developed to treat schizophrenia thanks to several earlier findings. They can correct NMDA hypofunction (which is hypothesised to occur in schizophrenia); DAO expression and activity are elevated in schizophrenia; and DAO may be a risk gene for schizophrenia. This study adds further evidence to suggest DAO inhibitors may be helpful in treating schizophrenia and is the first research to show that DAO has a direct impact on the dopamine systems function.

Paper Reference:

Schweimer J. V., Coullon G. S. L., Betts J. F., Burnet P. W. J., Engle S. J., Brandon N. J., Harrison P. J., Sharp T. (2014) Increased burst-firing in the ventral tegmental area dopaminergic neurons in D-amino acid oxidase knockout mice in vivo European Journal of Neuroscience, 40(7):2999-3009 doi: 10.1111/ejn.12667