Further evidence for altered myelin biosynthesis and glutamatergic dysfunction in schizophrenia.
Recent studies have provided evidence for neuronal and oligodendrocyte-related abnormalities being associated with schizophrenia. However, the functional interplay and causal relationship between these two abnormalities is poorly understood. In this report, we provide data that identify myelin and fatty-acid biosynthesis dysfunction in schizophrenia based on post-mortem brain studies (prefrontal cortex) utilizing parallel metabolic and transcriptomics investigations. We detected a significant up-regulation of N-acetylaspartate (NAA) by HPLC analysis. Microarray and Q-PCR investigations revealed mRNA abnormalities for several enzymes involved in NAA metabolism. Additionally, glutamatergic neurotransmission components were also found to be affected. Our results suggest that, apart from the previously reported alterations in myelin-related protein synthesis, myelin synthesis itself may be directly affected in schizophrenia as indicated by changes in key enzymes involved in NAA metabolism. A decrease in NAA catabolism in oligodendrocytes would severely reduce acetate levels required to produce myelin lipids and may subsequently affect glutamatergic neurotransmission.
Tkachev
Dmitri
D
Institute of Biotechnology, Tennis Court Road, Cambridge, UK.
Mimmack
Michael L
ML
Huffaker
Stephen J
SJ
Ryan
Margaret
M
Bahn
Sabine
S
D000328:Adult; D000368:Aged; D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D002102:Cadaver; D016022:Case-Control Studies; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D043425:Glutamate Carboxypeptidase II / Q000235:genetics / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009186:Myelin Sheath / Q000378:metabolism* / Q000473:pathology; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009435:Synaptic Transmission
D005227:Fatty Acids; D012333:RNA, Messenger; D018094:Receptors, Metabotropic Glutamate; C102718:metabotropic glutamate receptor 3; D001224:Aspartic Acid; D018698:Glutamic Acid; C000179:N-acetylaspartate; D043425:Glutamate Carboxypeptidase II; D000581:Amidohydrolases; C019751:aspartoacylase