Project Summary

Elizabeth Scarr, Ph.D. (Young Investigator 2005) of the Mental Health Research Institute of Victoria and the University of Melbourne, aims to study whether a mutation in the muscarinic Ml receptor (MIR) gene, which is associated with poor performance on specific cognitive tests, is associated with low levels of the receptor in the cortex of individuals with schizophrenia. The study will determine levels of muscarinic Ml receptors in post-mortem tissue using a variety of techniques. In addition, genotyping will find allelic variants of the receptor to determine if any of the polymorphisms affects the level of cortical MIR in subjects with schizophrenia. If demonstrated, this will be strong data to support the hypothesis that decreased cortical MIR contributes to some of the cognitive deficits associated with schizophrenia. Given recent studies showing that activation of the central cholinergic system can reverse some of the cognitive deficits in schizophrenia and schizotypal personality disorder, proving this hypothesis would imply that an agonist or partial agonist targeting the MIR could be a therapeutic strategy for cognitive problems in schizophrenia. Furthermore, knowing whether a MIR genotype was associated with low cortical levels of the receptor would allow usage of the variant as a peripheral marker to identify subjects with schizophrenia likely to have low cortical MIR and, hence, benefit from treatment targeting that receptor. Results from the study are particularly pertinent given the efforts to synthesize muscarinic receptor specific agonists for the treatment of schizophrenia.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia\Molecular

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