Understanding the contribution of cortical interneuron dysfunction to schizophrenia

精神障碍是发达国家15岁至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出现，并导致终生丧失能力或寿命缩短。因此，精神障碍是一个巨大的公共卫生挑战。目前治疗大多数精神疾病的药物只是治标不治本，这主要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发育性大脑疾病，主要有三组症状：(I)阳性(精神病、妄想和幻觉)，(Ii)消极(动机减少和社交退缩)，以及(Iii)认知(记忆和执行功能缺陷)。抗精神病药物可以控制一些患者的阳性症状，但对许多患者无效，对阴性症状影响不大，也无法改善认知缺陷。因此，开发新的治疗方法是一项迫切的未得到满足的需求。多条证据表明，精神分裂症是一种由遗传因素和环境应激源共同引起的大脑发育障碍。尽管近年来的进步极大地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汇聚，从而扰乱特定大脑回路的功能。在这种背景下，开发动物模型来测试精神分裂症潜在机制的特定假说是至关重要的，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，我们的目标是调查大脑皮层抑制电路发展的遗传和/或环境干扰如何可能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有关的神经回路异常。人们通常认为，精神分裂症的不同症状可能是通过不同大脑功能的独立改变而产生的。我们将进行实验来验证这一假设，即在精神分裂症中观察到的主要症状群中，至少有两个可能是由皮质抑制电路中断引起的。在目标2中，我们将分析大麻的使用如何影响一些皮质抑制回路的功能，这些回路已知特别容易受到与精神分裂症有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序如何影响病理轨迹。在目标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质抑制电路上的收敛。我们将进行生物信息学和功能分析，以研究其变异与人类精神分裂症有关的基因，并在这些细胞在大脑皮层发展连接的过程中由特定群体的中间神经元表达。识别精神分裂症中被病理基因变异和环境因素破坏的神经回路是开发针对精神分裂症的生物底物的新治疗干预措施的基本步骤。

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.