Potential pathophysiological role of d-amino acid oxidase in schizophrenia: immunohistochemical and in situ hybridization study of the expression in human and rat brain

Abstract

D-Amino acid oxidase (DAO) is a peroxisomal flavoenzyme that catalyzes oxidative deamination of a wide range of D-amino acids. Among the possible substrates of DAO in vivo, D-serine is proposed to be a neuromodulator of the N-methyl-D-aspartate (NMDA) type glutamate receptor. The gene for DAO was reported to be associated with schizophrenia. Since DAO is expected to be one of the key enzymes in the regulation of NMDA neurotransmission, the modulation of the enzyme activity is expected to be therapeutical for neuronal disorders. In search of the pathophysiological role of DAO, we analyzed the distribution of DAO mRNA and protein in the rat and human brain. In rat, the distribution of DAO mRNA was newly detected in choroid plexus (CP) epithelial cells in addition to glial cells of pons, medulla oblongata, and especially Bergmann glia of cerebellum. Moreover, to investigate how DAO expression level is altered in schizophrenia, we performed immunohistochemistry in the human brain. In agreement with the results in the rat brain, the immunoreactivity for DAO was detected in glial cells of rhombencephalon and in CP. Furthermore, higher level of DAO expression was observed in schizophrenic CP epithelial cells than that in non-schizophrenic cases. These results suggest that an increase in DAO expression in parts of the brain is involved in aberrant D-amino acid metabolism. In particular, gene expression of DAO in CP suggests that DAO may regulate D-amino acid concentration by modulating the cerebrospinal fluid and may be regarded as a potential therapeutic target for schizophrenia.

d-Amino Acid Oxidase Activity Is Inhibited by an Interaction with Bassoon Protein at the Presynaptic Active Zone

“…The interaction of DAO with BSN may be especially relevant in the forebrain, where DAO has been reported to be predominantly expressed in neurons (12,34,36,65). Such expression, in conjunction with our observation of an inhibitory effect of BSN on the activity of DAO, may in part explain why the enzymatic activity of DAO has been consistently undetectable in the forebrain (66,67).…”

“…DAO expression in humans shows predominant neuronal expression in the dorsolateral prefrontal cortex and hippocampus, neuronal and glial expression in substantia nigra pars compacta, and strong glial expression in cerebellum (12). In rodents, DAO message and protein have been reported in the same brain regions as in humans (34). On a subcellular level, DAO was first reported to be localized within liver peroxisomes, consistent with the presence of a peroxisomal targeting sequence located within the DAO polypeptide (35).…”

Metabolism of the neuromodulator d-serine

“…The results of the immunohistochemistry experiments on human brain tissues were in agreement with those obtained with rat samples: the staining corresponding to hDAAO was observed in glial cells of the rhomboencephalon and in the CP. hDAAO-immunopositive cells were detected in the molecular and Purkinje cell layers in the cerebellum, as previously reported [90], as well as in the CP, pons, and medulla oblongata sections, whereas only modest levels of immunoreactivity were observed within the cerebral cortex and in the spinal cord (both in the white and gray matter) [91]. It was suggested that the expression of hDAAO in CP epithelial cells, whose main function is to produce cerebrospinal fluid (CSF), is related to a specific regulatory mechanism governing D-serine levels in the CSF.…”

“…Most recently, Ono et al [91] analyzed in parallel the distribution of DAAO mRNA and protein in rat and human brain. Concerning DAAO expression in rat brain, the flavoprotein was detected in the prefrontal cortex and thalamus and its presence was also confirmed in the choroid plexus (CP) and hippocampus.…”

“…The first is that in human brain cortex DAAO immunoreactivity was observed both in glial cells [69] and in neurons [90], whereas it is largely-if not exclusivelyglial in the cerebellum [90,91]. The basis and significance for this still remain obscure.…”