The N-methyl-d-aspartate receptor co-agonist d-serine is synthesized by serine racemase and degraded by d-amino acid oxidase. Both d-serine and its metabolizing enzymes are implicated in N-methyl-d-aspartate receptor hypofunction thought to occur in schizophrenia. We studied d-amino acid oxidase and serine racemase immunohistochemically in several brain regions and compared their immunoreactivity and their mRNA levels in the cerebellum and dorsolateral prefrontal cortex in schizophrenia. dAmino acid oxidase immunoreactivity was abundant in glia, especially Bergmann glia, of the cerebellum, whereas in prefrontal cortex, hippocampus and substantia nigra, it was predominantly neuronal. Serine racemase was principally glial in all regions examined and demonstrated prominent white matter staining. In schizophrenia, d-amino acid oxidase mRNA was increased in the cerebellum, and as a trend for protein. Serine racemase was increased in schizophrenia in the dorsolateral prefrontal cortex but not in cerebellum, while serine racemase mRNA was unchanged in both regions. Administration of haloperidol to rats did not significantly affect serine racemase or d-amino acid oxidase levels. These findings establish the major cell types wherein serine racemase and d-amino acid oxidase are expressed in human brain and provide some support for aberrant d-serine metabolism in schizophrenia. However, they raise further questions as to the roles of d-amino acid oxidase and serine racemase in both physiological and pathophysiological processes in the brain.

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contributed equally to this work NRIF (neurotrophin receptor interacting factor) is a ubiquitously expressed zinc finger protein of the Krü ppel family which interacts with the neurotrophin receptor p75 NTR . The interaction was first detected in yeast and then biochemically confirmed using recombinant GST-NRIF fusions and p75 NTR expressed by eukaryotic cells. Transgenic mice carrying a deletion in the exon encoding the p75 NTRbinding domain of NRIF display a phenotype which is strongly dependent upon genetic background. While at the F 2 generation there is only limited (20%) embryonic lethality, in a congenic BL6 strain nrif -/-mice cannot survive beyond E12, but are viable and healthy to adulthood in the Sv129 background. The involvement of NRIF in p75 NTR /NGF-mediated developmental cell death was examined in the mouse embryonic neural retina. Disruption of the nrif gene leads to a reduction in cell death which is quantitatively indistinguishable from that observed in p75 NTR-/-and ngf -/-mice. These results indicate that NRIF is an intracellular p75 NTRbinding protein transducing cell death signals during development.

Background: Evidence of genetic association between the NRG1 (Neuregulin-1) gene and schizophrenia is now well-documented. Furthermore, several recent reports suggest association between schizophrenia and singlenucleotide polymorphisms (SNPs) in ERBB4, one of the receptors for Neuregulin-1. In this study, we have extended the previously published associations by investigating the involvement of all eight genes from the ERBB and NRG families for association with schizophrenia.