Increased burst‐firing of ventral tegmental area dopaminergic neurons ind‐amino acid oxidase knockout micein vivo

Abstractd‐Amino acid oxidase (DAO) degrades theN‐methyl‐d‐aspartate (NMDA) receptor co‐agonistd‐serine, and is implicated in schizophrenia as a risk gene and therapeutic target. In schizophrenia, the critical neurochemical abnormality affects dopamine, but to date there is little evidence thatDAOimpacts on the dopamine system. To address this issue, we measured the electrophysiological properties of dopaminergic (DA) and non‐DAneurons in the ventral tegmental area (VTA) of anaesthetisedDAOknockout (DAO−/−) andDAOheterozygote (DAO+/−) mice as compared with their wild‐type (DAO+/+) littermates. Genotype was confirmed at the protein level by western blotting and immunohistochemistry. One hundred and thirty‐nineVTAneurons were recorded in total, and juxtacellular labelling of a subset revealed that neurons immunopositive for tyrosine hydroxylase hadDA‐like electrophysiological properties that were distinct from those of neurons that were tyrosine hydroxylase‐immunonegative. InDAO−/−mice, approximately twice as manyDA‐like neurons fired in a bursting pattern than inDAO+/−orDAO+/+mice, but other electrophysiological properties did not differ between genotypes. In contrast, non‐DA‐like neurons had a lower firing rate inDAO−/−mice than inDAO+/−orDAO+/+mice. These data provide the first direct evidence thatDAOmodulatesVTA DAneuron activity, which is of interest for understanding both the glutamatergic regulation of dopamine function and the therapeutic potential ofDAOinhibitors. The increasedDAneuron burst‐firing probably reflects increased availability ofd‐serine atVTA NMDAreceptors, but the site, mechanism and mediation of the effect requires further investigation, and may include both direct and indirect processes.