Grant: Project Grant

Schizophrenia is a debilitating mental illness affecting approximately 1% of the world population. It is one of the leading causes of long-term disability, costing the Canadian health care system approximately $7 billion per year in medical care and lost productivity. One of the major obstacles in developing new therapeutics for schizophrenia is a lack of understanding of the cellular basis of the disease. Studies with schizophrenia brains consistently show deficits in inhibitory neurons in the prefrontal cortex and hippocampus. Despite this important link, little is known about how such dysfunctional inhibitory neurons contribute to schizophrenia and whether one can rescue behavioural impairments by restoring the neuron dysfunction. The proposed experiments are aimed at addressing this knowledge gap. We will first study the changes in the important characteristics of inhibitory neurons (known as CCK-GABA cells) in well-established mouse models of schizophrenia. Next, using light-mediated neuron silencing and imaging, we will demonstrate its causal contribution to cognitive symptoms of schizophrenia and determine how their activity dynamically change during working memory task. Lastly, we will explore the therapeutic benefit of activating inhibitory neurons as a treatment of behavioural impairments. To this end, we have established a highly selective genetic method called the intersectional approach. This innovative tool allows us to examine systemically the core features of specific inhibitory neuron subtypes and manipulate their activity in freely behaving animals. The proposed research is an essential step for identifying pathophysiologically-based targets for novel therapeutic interventions for schizophrenia. If successful, it will lead to a better understanding of how distinct cortical interneuron subtypes contribute to schizophrenia and reveal novel treatment strategies that aim at correcting the underlying neural circuit deficits.