Tkachev1,3, Michael L. Mimmack1,3, Margaret M. Ryan1,3,

Matt Wayland2, Tom Freeman2, Maree J. Webster4,

Robert H. Yolkne5, and Sabine Bahn1,3

1Department of

Neurobiology, Babraham Institute, Cambridge CB2 4AT, UK; 2UK Human

Genome Mapping Project Resource Centre, Hinxton, Cambridge CB10 1SB, UK; 3Department

of Psychiatry, University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2

2QQ, UK; 4Stanley Laboratory of Brain Research, Department of

Psychiatry, Uniformed Services University for the Health Sciences, 4301 Jones

Bridge Road, 20814-4709, Bethesda, MD, USA; 5Stanley Division of

Developmental Neurovirology, Johns Hopkins School of Medicine, Baltimore, MD

21205, USA



BACKGROUND:  The glutamate hypothesis of schizophrenia has been one of the

prominent theories for many years.  Other evidence also suggests a GABAergic

dysfunction in schizophrenia.  To add to the puzzle, several independent gene

expression-profiling studies have recently found abnormalities in the expression

of myelin- and oligodendrocyte-specific genes. Here we provide evidence from

post-mortem brain studies that suggest abnormalities in the metabolism of

several amino acids, which are closely linked to myelination, Glutamatergic and

GABAergic neurotransmission based on parallel metabolic and transcriptomics




HPLC methods were employed to measure and compare the concentrations of NAA,

Glu, Asp, Arg, Gly, Cit, Tau, and GABA. Microarrays and Q-PCR were used to

examine expression levels of enzymes associated with the metabolites that showed

a significant change.



We have identified differences for the following metabolites: NAA, Asp, and Arg

were up-regulated, GABA was down-regulated.  Microarray and quantitative PCR

revealed abnormalities at the mRNA level for several key enzymes involved in the

metabolism of these metabolites.


CONCLUSIONS:  Our results suggest multiple abnormalities in the amino acid

metabolism in schizophrenia resulting in changes in metabolite concentrations. 

This was associated with the transcriptional dysregulations of key enzymes

involved in the turnover of these metabolites.


This work was supported

through a centre grant by the Stanley Medical Research Institute