Understanding the contribution of cortical interneuron dysfunction to schizophrenia

精神疾病是发达国家15至49岁人群疾病负担的主要来源。与心脏病或大多数形式的癌症不同，自闭症或精神分裂症等疾病在生命早期就开始了，并导致终身残疾或寿命缩短。因此，精神疾病是一个巨大的公共卫生挑战。目前对大多数精神疾病的药物治疗仅仅是治标不治本，很大程度上是因为我们对其病因的了解有限。精神分裂症是一种复杂的脑部发育障碍，主要有三类症状：(i)阳性症状（精神病、妄想和幻觉），（ii）阴性症状（动机降低和社交退缩），以及（iii）认知症状（记忆和执行功能缺陷）。抗精神病药物在一些患者中控制阳性症状，但在许多患者中无效，对阴性症状有适度影响，并且不能改善认知缺陷。因此，开发新的治疗方法是一个迫切的未满足的需求。多种证据表明，精神分裂症是一种由遗传因素和环境压力因素共同引起的大脑发育障碍。尽管近年来的进步大大增加了我们对遗传和环境风险的理解，但我们不知道这些因素在发育过程中如何聚集在一起，破坏特定大脑回路的功能。在这种情况下，开发动物模型来测试精神分裂症潜在机制的特定假设是至关重要的，因为在人类研究中达到所需的分辨率水平目前是不可行的。在这个项目中，我们的目标是研究大脑皮层抑制回路发育的遗传和/或环境破坏如何导致与精神分裂症相关的功能和行为改变。我们提出的研究有三个目标：在目标1中，我们将研究可能与不同精神分裂症症状相关的神经回路异常。人们通常认为，精神分裂症的不同症状可能是由于不同脑功能的独立改变而引起的。我们将进行实验来验证这样一个假设，即在精神分裂症中观察到的至少两种主要症状簇可能是由皮层抑制回路的破坏引起的。在目标2中，我们将分析大麻使用如何影响一些皮层抑制回路的功能，这些回路已知特别容易受到与精神分裂症相关的病理基因变异的影响。我们将在不同的发育窗口进行这些实验，这将允许测试发育时间如何影响病理特征。在Aim 3中，我们将系统地探索与精神分裂症相关的基因网络，并探索它们在特定皮层抑制回路上的收敛。我们将进行生物信息学和功能分析，以研究与人类精神分裂症有关的基因变异，并在这些细胞在大脑皮层中形成连接期间由特定的中间神经元群体表达。识别精神分裂症中被病理性基因变异和环境因素破坏的神经回路，是开发针对该疾病生物学基础的新型治疗干预措施的基础。

Psychiatric disorders represent the leading source of disease burden in the developed world for people between ages 15 and 49. In contrast to heart disease or most forms of cancer, diseases such as autism or schizophrenia begin early in life and contribute to lifelong incapacity or reduced longevity. Consequently, psychiatric disorders are a great public health challenge. Current medications for most psychiatric disorders are merely palliative, largely because of our limited understanding of their causes. Schizophrenia is a complex developmental brain disorder with three main clusters of symptoms: (i) positive (psychosis, delusions and hallucinations), (ii) negative (reduced motivation and social withdrawal), and (iii) cognitive (memory and executive function deficits). Antipsychotic drugs control positive symptoms in some patients, but are ineffective in many, have a modest impact on negative symptoms, and fail to improve cognitive deficits. Consequently, the development of new therapies is an urgent unmet need.Multiple lines of evidence suggest that schizophrenia is a disorder of brain development caused by a combination of genetic factors and environmental stressors. Although advances in recent years have massively increased our understanding of genetic and environmental risks, we do not know how these factors converge during development to disrupt the function of specific brain circuits. In this context, the development of animal models for testing specific hypotheses on the mechanisms underlying schizophrenia is crucial, because achieving the required level of resolution in human studies is currently unfeasible.In this project, we aim to investigate how genetic and/or environmental disruption of the development of inhibitory circuits in the cerebral cortex may lead to the functional and behavioural alterations associated to schizophrenia. Our proposed research has three objectives:In Aim 1, we will investigate neural circuit abnormalities that may link different schizophrenia symptoms. It has been often assumed that different symptoms in schizophrenia may arise through independent alterations in different brain functions. We will carry out experiments to test the hypothesis that at least two of the main clusters of symptoms observed in schizophrenia might be caused by disruption of cortical inhibitory circuits. In Aim 2, we will analyse how cannabis use may impact the function of some of the cortical inhibitory circuits that are known to be particularly susceptible to pathological gene variation linked to schizophrenia. We will carry out these experiments in different developmental windows, which will allow testing how developmental timing influences pathological traits.In Aim 3, we will systematically explore gene networks linked to schizophrenia and probe their convergence on specific cortical inhibitory circuits. We will carry out bioinformatic and functional analyses to study genes whose variation has been linked to schizophrenia in humans and are expressed by specific populations of interneurons during the period that these cells develop their connections in the cerebral cortex.Identifying the neural circuits that are disrupted by pathological gene variation and environmental factors in schizophrenia is a fundamental step towards the development of novel therapeutical interventions that target the biological substrates of the disorder.