Targeted lipidomics and metabolomics evaluations of cortical neuronal stress in schizophrenia.

BACKGROUND

Cortical neuronal dysfunction has been proposed to underlie the psychopathology and cognitive dysfunction of schizophrenia. Previously we have reported altered sphingolipid and N-acylphosphatidylserine (NAPS) metabolism in the frontal cortex in schizophrenia. We continue to expand these investigations to define the biochemical basis for these critical neuropathologies.

METHODS

We undertook a targeted high resolution mass spectrometric analysis to validate our previous reports of elevated sphingolipids and NAPS in the frontal cortex of a new cohort of schizophrenia subjects. Furthermore we expanded these analyses to include ceramides, N-acylphosphatidylethanolamines (NAPE), and N-acylethanolamines (NAE). In the same tissue samples we examined N-acetylaspartylglutamate (NAAG), a modulator of excitatory amino acid transmission, hypothesized to be involved in the pathology of schizophrenia.

RESULTS

We repeated our observations of elevated sulfatides in the frontal cortex in schizophrenia. An in-depth analysis of other sphingolipids revealed decrements in ceramide levels and increased levels of lactosylceramides. NAPS also were found to be augmented in schizophrenia as we previously reported. In addition, levels of NAPES, established biomarkers of neuronal stress, were elevated while their metabolites, NAEs were decreased. With regard to excitatory amino acid neurotransmission, NAAG levels were decreased by 50% while the metabolic precursor, N-acetylaspartate was unaltered.

CONCLUSIONS

Our data support the concept of cortical neuronal dysfunction in schizophrenia as indicated by altered metabolism of structural sphingolipids and NAAG, a modulator of excitatory amino acid neurotransmission.