Predicting antipsychotics response in an animal model investigating neuroimmune-dopamine interactions and its translation into a schizophrenia patient cohort

到目前为止，从精神分裂症动物模型的分子发现到精神分裂症患者的转化取得的成功并不大，这引发了人们对精神病学转化研究总体价值的质疑。治疗抵抗是精神分裂症的一个严重问题，许多患者对一线抗精神病药物没有反应。该项目展示了一种解决翻译精神病学困难的方法，包括深化对神经免疫-多巴胺相互作用的了解，识别精神分裂症亚群的特定免疫生物型，以及能够预测精神分裂症患者对抗精神病药物的治疗反应的血液测试。我们之前开发了散发性精神分裂症的转基因大鼠模型，其错误组装的DISC1蛋白信号受损，具有与精神分裂症相关的神经解剖学、神经化学和与异常的多巴胺稳态相关的行为表型。我们在这个动物模型中确定了能够预测具有高度特异性的精神分裂症患者子集的血液生物标志物。氯氮平在这一亚群中的过度使用，以及在这个动物模型中裸体样酶活性的降低，类似于治疗难治性精神分裂症，都支持这样的假设，即动物模型可能是第一个建立难治性精神分裂症模型的动物模型，并且相关的、可翻译的免疫生物型可能表明对抗精神病药物的治疗反应。在这项提案中，将测试1.用阿米苏普利或氯氮平进行药物治疗是否能不同地挽救动物模型的关键行为表型，是否可以使用行为、神经解剖学和神经炎症读数来定义该动物模型中治疗抵抗的表型，以及是否可以通过血液生物标记物来预测治疗反应。2.将对现有的动物模型进行修改，以建立行为障碍的两次打击模型，其中母体免疫激活添加到已经受损的信号通路中。来自实验1和实验2的外周血液的RNAseq产生的免疫特征将被转化为可用的联合队列中的精神分裂症患者，其中可以获得受控抗精神病药物治疗之前的血液。联合队列是一个现有的独立和完成的BMBF项目，旨在前瞻性地测试阿米舒普利/奥氮平联合治疗相对于单一治疗的临床治疗反应。在该项目结束时，将获得与多巴胺稳态、行为、免疫生物型和抗精神病药物治疗反应相关的DISC1蛋白介导的信号相互作用网络的基本见解。此外，外周血中一种明显的免疫生物型将被识别出来，这可能与预测抗精神病药物治疗的临床反应高度相关。

The success of translation from molecular discoveries in animal models of schizophrenia to schizophrenia patients has so far been modest and this has raised questions on the value of translational research in psychiatry in general. Treatment resistance is a serious problem in schizophrenia where many patients do not respond to first line antipsychotics. This project shows a way out of the difficulties of translational psychiatry towards deepening insight into neuroimmune-dopamine interactions, identifying a specific immune biotype for a schizophrenia subset, and a blood test able to predict treatment response to antipsychotics in schizophrenia patients.We previously developed a transgenic rat model for sporadic schizophrenia with impaired signaling of the misassembled DISC1 protein featuring schizophrenia-relevant neuroanatomica, neurochemical and behavioral phenotypes related to aberrant dopamine homeostasis. We identified blood biomarkers in this animal model that were able to predict a subset of schizophrenia patients with high specificity. Both, overrepresentation of clozapine use in this subset, as well as decreased NudE-like 1 anzyme activity in this animal model, similar to treatment-resistant schizophrenia, support the hypothesis that animal model may be the first to model treatment-resistant schizophrenia, and that the associated, translatable immune biotype may indicate treatment response to antipsychotics.In this proposal, it will be tested 1. whether pharmacotherapy with amisulpride or clozapine differentially rescues key behavioral phenotypes of the animal model, whether a phenotype of treatment resistance in this animal model can be defined using behavioral, neuroanatomical and neuroinflammatory readouts, and whether the therapy response can be predicted by blood biomarkers. 2. The existing animal model will be modified to establish a two-hit model of a behavioral disorder where maternal immune activation is added to the already impaired signaling pathways. RNAseq-generated immune signatures from peripheral blood of experiments 1 and 2 will be translated into schizophrenia patients of the available COMBINE cohort from which blood prior to controled antipsychotics therapy is available. The COMBINE cohort is an existing independent and completed BMBF project aiming to prospectively test the clinical therapy response a amisulpride / olanzapine combination therapy over monotherapy of each antipsychotic.At the end of this project, fundamental insights into the interaction network of DISC1 protein-mediated signaling relevant for dopamine homeostasis, behavior, immune biotypes and response to antipsychotic treatment will be been gained. In addition, an immune biotype apparent in peripheral blood will have been identified that is potentially highly relevant for predicting clinical response for antipsychotic treatment.