[Frontiers in Bioscience 16, 1797-1810, January 1, 2011] 1797 Sphingolipid abnormalities in psychiatric disorders: a missing link in pathology? Sujatha Narayan, Elizabeth A. Thomas Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037 TABLE OF CONTENTS 1. Abstract 2. Introduction 3. What are sphingolipids? 3.1. Ceramide (n-acylsphingosine) metabolism 3.2. Sphingomyelin 3.3. Glycosphingolipids 3.3.1. Glucosylceramides 3.3.2. Galactosylceramides 4. Sphingolipids and lipid rafts 5. Evidence for involvement of sphingolipid abnormalities in psychiatric disorders 5.1. Glycolipid storage disorders with psychiatric features 5.2. Studies on schizophrenia 5.3. Studies on schizophrenia and bipolar disorder 5.4. Studies on depression 6. Sphingolipids as a missing link between molecular and clinical abnormalities in schizophrenia 6.1. CNS development 6.2.. Oligodendrocyte/myelin function 6.2.1. Oligodendrocyte development 6.2.2. Myelin structure and function 6.2.3. Neuron-glia interactions 6.3 Synaptic Neurotransmission 6.3.1. G Protein-coupled receptors and lipid rafts 6.3.2. Synaptic machinery 6.4. Immune /inflammatory pathways 7. Perspectives 8. References 1. ABSTRACT Sphingolipids are biologically active lipids ubiquitously expressed in all vertebrate cells, especially those in the CNS. Aside from their essential roles as structural components of cell membranes, studies over the past two decades have shown that they play vital roles in cellular signaling, cell differentiation and proliferation, apoptosis and inflammation. Given these properties, it is not surprising that disruption of sphingolipid metabolism is strongly associated with several diseases that exhibit diverse neurological, psychiatric, and metabolic consequences. Here, we review the emerging roles of sphingolipids in disease pathogenesis in psychiatric disorders, including schizophrenia, bipolar disorder and major depression. Understanding sphingolipid metabolism and it dysregulation in human disease is significant for the development of new therapeutic approaches. 2. INTRODUCTION Major advances in sphingolipid research over the past 20 years have transformed our understanding of this class of lipid molecules and have uncovered many roles for glycolipids in both the basic functioning of the brain under normal conditions and in disease states. In addition to their roles as structural components of cell membranes, sphingolipids are now known to play vital roles in cellular signaling, cell-to-cell interactions, apoptosis and inflammation, and have been found to modulate developmental processes, such as cell differentiation and proliferation. Many of these functions have been associated with the pathology of human diseases. Genetic mutations in the genes encoding several of the enzymes of sphingolipid metabolism result in lysosomal storage diseases, including Fabry disease, Farber