The role of cholesterol synthesis in the mode of action of clozapine in schizophrenia models

Abstract

Schizophrenia is considered a multifactorial psychiatric disorder that involves environmental, genetic, and neurodevelopmental dysfunctions. The schizophrenia pathophysiology includes molecular abnormalities in immune, metabolic, and endocrine systems. Despite significant progress in the comprehension of the various manifestations of schizophrenia, the etiology of schizophrenia remains unclear. Several studies have implicated oligodendrocyte dysfunction and myelin alterations in this disorder. Recently, some studies proposed that oligodendrocytes are central to energy metabolism dysfunctions in schizophrenia brains. Currently, the major therapeutic strategy relies on the use of antipsychotic drugs. Nevertheless, the effects of antipsychotics on glial cells, especially oligodendrocytes, remains unknown. Previously proteomic studies have shown that Clozapine (atypical antipsychotic) up-regulates the cholesterol synthesis enzyme (hydroxymethylglutaryl CoA synthase or HMG-CoA synthase) activity in oligodendrocytes. Cholesterol in the brain plays an important role in myelin production and oligodendrocyte metabolism. Cholesterol synthesis is regulated by the transcription factor SREBP2 (sterol regulatory element-binding protein 2) and insulin, antipsychotic targets associated with clozapine therapeutics effects. Furthermore, cholesterol metabolism has been implicated in the regulation of many processes, including the myelin membrane growth, axon wrapping, and synapse formation. These functions are essential to brain physiological homeostasis. In this context, the role of oligodendrocytes in schizophrenia and the mode of action of antipsychotics, the project aims to evaluate the role of cholesterol synthesis in the Clozapine effects through in vitro and in vivo experimental schizophrenia's models. For this, male C57BL/6 mice will be exposed to the Cuprizone diet, a neurotoxin that causes demyelination in various regions of the central nervous system. The in vitro model will be studying through oligodendrocyte cultures from mice neonates. Both models will be treated with Clozapine and the HMG-CoA reductase inhibitor, Simvastatin. The objective is to evaluate that the depletion of cholesterol synthesis impairs the Clozapine effect through proteomics, molecular, and behavioral analysis. Finally, we propose to contribute to the understanding of the molecular mechanisms involved with the action of antipsychotics through the integration of biochemical pathways, as well as to improve understanding of the development of schizophrenia and finding new targets for drug discovery. (AU)