Phospholipid metabolism in neuropsychiatric disorders

Abstract

The physicochemical properties of the neuronal membrane have a major impact on neural cell metabolism, affecting brain function and plasticity. As a continuation of former and recent work on this field, the primary objective of this project is to investigate the membrane phospholipid metabolism in three neuropsychiatric diseases, namely schizophrenia, Alzheimer's disease (AD) and temporal lobe epilepsy. We are particularly interested on the neurobiology of phospholipase A2 (PLA2), the main phospholipid-cleaving enzyme in neurons, and its effects on the composition and properties of the neuronal membrane. Previous data from our group and others have consistently shown that PLA2 activity is increased in schizophrenics, and reduced in AD. Such abnormality, which can be further detected in peripheral blood platelets, correlate with discrete clinical and pathological findings. In schizophrenia, increased PLA2 activity was shown to be associated with negative symptoms, suggesting greater frontal lobe dysfunction. In platelet membranes of schizophrenics, PLA2 hyperactivity (and abnormal precursor and metabolite levels) was reverted after neuroleptic treatment. In AD post-mortem brains, lower cerebral PLA2 levels were correlated with higher counts of senile plaques and neurofibrillary tangles. Lower platelet PLA2 activity was further correlated with the severity of cognitive decline in AD, and predicted a more deteriorating outcome. Likewise, abnormal in vivo cerebral phospholipid turnover, as detected by 31P-spectroscopy scans, was associated with a worse performance on neuropsychological tests in AD. We propose a multidisciplinary project in order to investigate the genetic determinants and biological modulators of membrane phospholipid metabolism, addressing the clinical neurobiology of three major neuropsychiatric disorders. The genetic and biochemical regulation of phospholipid metabolism will be addressed in vitro and in vivo with the aid of laboratory techniques, primary neuronal cultures, and animal models. Biological samples obtained from patients in each group will be evaluated in the light of the respective clinical findings, focusing on psychopathology, cognitive neuropsycology, electrophysiology, and functional neuroimaging... (AU)