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.

The pathophysiology of schizophrenia remains poorly understood, but defects in cortical interneurons -primarily in Parvalbumin-expressing (PV+) interneurons- are among the most replicated neuropathological findings. In addition, functional studies in humans have shown gamma oscillatory activity is abnormal in schizophrenia patients. Since work in rodents have demonstrated that PV+ interneurons are required for gamma oscillations, these findings reinforce the notion that PV+ interneurons are central to the disease process in schizophrenia.

We aim to understand how pathological genetic variation and environmental risk factors converge during brain development to disrupt the function of cortical inhibitory neurons in at least a fraction of schizophrenia patients. We will use mice in this research programme because this is the animal model most amenable to genetic manipulation with brain circuits resembling those found in humans. The proposed research programme has three objectives: (1) To analyse the neural circuit mechanisms linking PV+ interneuron dysfunction to striatal hyperdopaminergia, (2) To investigate the neural circuit mechanisms through which genetic risk and adverse environmental factors may interact to disrupt cortical inhibitory circuits, and (3) To determine how gene networks linked to schizophrenia influence the development and function of PV+ interneurons in the cerebral cortex.

Our proposed research builds on recent findings from our laboratories and capitalises on recent human genetic and epidemiological studies to bridge the gap between causes and mechanisms in schizophrenia. Successful execution of this research programme may lead to novel strategies for the development of new pharmacological treatments for schizophrenia.

Who will benefit from this research?

The cognitive and mental problems characteristic of young adults that suffer from schizophrenia have a long-lasting impact on the affected individuals, their families and society in general, from health services to community services.

How will they benefit from this research?

We have identified six possible benefits from our research, as outlined below:

Impact 1. Establishing a link between cognitive deficits and psychosis in schizophrenia. Our research aims at connecting different symptoms at the level of specific neural circuit alterations. Demonstrating such a link will impact the design and testing of new treatments.

Impact 2. Understanding the neural circuit deficits that mediate the influence of environmental stressors in schizophrenia. Elucidating the neurobiological substrate of gene-environment interactions in schizophrenia will impact the development of new treatments and policy strategies, including for example prevention programmes for individuals at high risk for psychosis.

Impact 3: Identifying vulnerable cell types through the analysis of gene networks linked to schizophrenia. Our research programme will accelerate the discovery of disease mechanisms by building on the recent progress of human genetics to advance from the analysis of the function of individual disease genes to gene networks. The identification and characterisation of these gene networks will exponentially increase the number of potential targets for new pharmacological treatments.

Impact 4: Strengthening the links between basic and clinical research. Our research programme will establish the basis for a novel model of collaboration between basic and clinical researchers, which will have an impact in the development of new research programmes.

Impact 5: Improving training in neurodevelopmental disorders. Our research programme will enhance the training of staff in our laboratories by increasing interactions with clinical colleagues and international experts.

Impact 6: Public engagement and communication. Through our participation in outreach activities, we will raised public awareness on mental health and improve the progression and success of students currently under-represented at our university and other institutes of higher education.

Details including metrics of success and deliverables are provided in the Pathways to Impact section.