Understanding the contribution of cortical interneuron dysfunction to schizophrenia

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.