Muscarinic M1 receptor, cognition and schizophrenia

精神分裂症是一种严重的精神疾病，影响着澳大利亚约1%的人口。虽然精神分裂症的显著症状是精神病，但大多数精神分裂症患者也表现出认知障碍。与精神病症状不同，认知障碍对目前的抗精神病药物治疗反应不佳。近十年来，我们一直在研究一种被称为M受体的受体家族的变化在精神分裂症病理中的可能作用。我们的研究表明，M受体家族的两个成员，M1和M4受体，在精神分裂症受试者的不同脑区可能有不同程度的减少。最近，我们发现在精神分裂症患者的背外侧前额叶皮质，减少的M受体是M1受体。自从我们发现这一点以来，另一个研究小组已经证明，M1受体的突变可能是精神分裂症认知缺陷的原因之一。我们现在正在提议一项研究，利用对死后脑组织和精神分裂症活体受试者的平行研究流来确定皮质M1受体减少可能是精神分裂症认知缺陷的原因。这将涉及确认M1受体的突变，使用来自白细胞的DNA测量，与精神分裂症的认知障碍有关。同时，我们将确定同样的突变是否与死后精神分裂症受试者大脑皮质中低水平的M1受体有关。如果这两个都是真的，这将为我们提供一个强有力的平台，表明低水平的皮质M1受体与精神分裂症的认知缺陷有关。

Schizophrenia is a serious psychiatric illness that affects approximately 1% of Australia's population. Whilst the prominent symptom of schizophrenia is psychosis, the majority of subjects with schizophrenia also show deficits in cognition. Unlike psychotic symptoms, deficits in cognition do not respond well to current antipsychotic drug treatment. We have been investigating the possible role for changes in a family of receptors, called muscarinic receptors, in the pathology of schizophrenia for almost a decade. Our research has shown that two members of the muscarinic receptor family, the M1 and M4 receptors, may be differentially decreased in different brain regions of subjects with schizophrenia. Recently, we have shown that in the dorsolateral prefrontal cortex, the muscarinic receptor that is decreased in schizophrenia is the M1 receptor. Since we made this discovery another group has shown that a mutation in the M1 receptor may be a cause of cognitive deficits in schizophrenia. We are now proposing a study using parallel streams of research on postmortem brain tissue and in living subjects with schizophrenia to determine the likelihood that decreases in M1 receptors in the cortex may be the cause of cognitive deficits in schizophrenia. This will involve confirming that mutations in the M1 receptor, measured using DNA from white blood cells, are associated with cognitive deficits in schizophrenia. At the same time we will determine if the same mutation is associated with low levels of M1 receptors in cortex obtained postmortem from subjects with schizophrenia. If both these are true this will give us a strong platform to suggest that low levels of cortical M1 receptors are associated with cognitive deficits in schizophrenia.