American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 119B:2–6 (2003) Rapid Publication Reduced Expression of the Muscarinic 1 Receptor Cortical Subtype in Schizophrenia D. Mancama, 1 * MJ. Arranz, 1 S. Landau, 2 and R. Kerwin 1 1 Section of Clinical Neuropharmacology, Department of Psychological Medicine, Institute of Psychiatry, De Crespigny Park, London, England, UK 2 Department of Biostatistics and Computing, Institute of Psychiatry, De Crespigny Park, London, England, UK The involvement of specific pathways medi- ated through muscarinic receptor activity has been widely implicated in schizophre- nia. Extensive pharmacological evidence supports the systems role in mediating anti- psychotic drug efficacy, while mounting physiological evidence demonstrates the presence of significant alterations to normal muscarinic receptor integrity in the disor- der. The mechanisms that facilitate the systems involvement and their magnitude, however, remain poorly understood. We have proposed that alterations to normal muscarinic receptor expression exist in schizophrenia, and that these significantly influence the physiological changes often reported for the system amongst patients. In this study, we investigate this potential, and have selected to examine the muscarinic 1 receptor, which constitutes a major target for antipsychotic action and plays a conspic- uous role in those regions central to the disorders pathophysiology. Using relative gene quantification, we measured post-mor- tem levels of steady-state cortical muscari- nic 1 receptor cDNA in patients (N ¼ 20) and unaffected controls (N ¼ 20), and examined group differences in expression levels. Com- mensurate with our hypothesis, we observed significant reductions in muscarinic 1 re- ceptor cDNA in our patient sample (F(1,37) ¼ 4.73, P ¼ 0.036) and have estimated this to constitute a 28% decrease compared to the control subjects (95% CI from 2 to 47%). These results provide evidence in support of altered muscarinic 1 receptor expression in schizophrenia, though further work is needed to corroborate these findings. ß 2003 Wiley-Liss, Inc. KEY WORDS: muscarinic receptor; schizo- phrenia; prefrontal cortex; gene expression INTRODUCTION Within the CNS, pathways mediated through mus- carinic receptor actions are thought to play a pivotal role in the cognitive functions of attention, learning, and memory [Hagan, 1987; Whittaker, 1988; Aigner, 1995; reviewed [van der Zee and Luiten, 1999; Felder et al., 2001]. These functions are particularly relevant to schizophrenia, having been shown to be integral to the disorder’s pathophysiology. The origins of impaired cognition in schizophrenia are unclear, but have become a major focus of attention partly given the inextricable link which exists between the dysfunction and both level of social functioning and a poor long-term prognosis [Gold and Weinberger, 1995; Weickert et al., 2000; Barch et al., 2001]. The likely involvement of central muscarinic activity has largely been demonstrated through pharmacological investigation, where selective antagonists such as pirenzepine and scopolamine, which specifically target and disrupt normal muscarinic 1(CHRM1) receptor function, dose dependently impair spatial learning, and short term memory [Bartus and Johnson, 1976; Hagan et al., 1987]. Administration of these agents has also been found to exacerbate existing symptomatology in schizophrenic patients while acet- ylcholine and cholinergic agonists often lead to a transient improvement in psychotic symptoms [Singh et al., 1985]. A significant proportion of conventional and atypical antipsychotics possess moderate to high affinity for muscarinic receptors, with clozapine for example displaying significantly higher selectivity at the *Correspondence to: Dr. D. Mancama, Section of Clinical Neuropharmacology, Department of Psychological Medicine, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, England. E-mail: sphadtm@iop.kcl.ac.uk Received 24 July 2002; Accepted 15 January 2003 DOI 10.1002/ajmg.b.20020 ß 2003 Wiley-Liss, Inc.