Schizophrenia is a debilitating disease that afflicts 1% of the US population. Symptoms of schizophrenia are classified into three categories: positive (delusions and hallucinations), negative (flattened affect, social isolation) and cognitive (impaired attention, executive function, working memory). Existing antipsychotics, while effective at treating the positive symptoms, do not treat the negative or cognitive symptoms of schizophrenia making them a significant unmet medical need. One of the challenges in discovering effective therapies for CNS diseases is development of preclinical assays that accurately model human cognitive processes. Traditional cell-based functional assays that model a specific target molecule or pathway implicated in a disease do not recapitulate the complex cellular and network processes underlying cognition. We propose the development of a novel in vitro brain slice screening platform that exploits the conservation of brain circuitry and functionality from rodents to humans. For example, human functional imaging and electroencephalographic studies have shown that higher cognitive functions, such as attention and working memory are associated with synchronized neuronal oscillations in the prefrontal cortex (PFC), particularly in the gamma frequency range (30-90Hz). Many of the cognitive impairments associated with schizophrenia are accompanied by a disruption of neural oscillations in the PFC. We have established an in vivo electrophysiological recording assay in freely behaving mice and have observed a significant alteration of gamma oscillations in the PFC of a genetic (calcineurin knockout) model of schizophrenia during the performance of attentional and mnemonic tasks. Our observations indicate that neural oscillations recorded from the PFC of rodents in vivo can provide a robust and objective measure of cognition. As a first step towards modeling the complex neural activity associated with cognition in an in vitro assay, we have begun to develop higher throughput in vitro electrophysiological methods based on multielectrode array technology. Using acute brain slices that preserve adult network connectivity, we can recapitulate the same high-frequency synaptic activity associated with cognitive processing in vivo. Our preliminary data indicate that alterations in gamma oscillations observed in vivo are also observed in vitro, suggesting good feasibility in translating in vivo electrophysiological endophenotypes into in vitro screening assays. These in vitro assays will permit testing of compound efficacy on processes important for cognition at much earlier stages of development, mitigating many of the risks associated with preclinical in vivo pharmacology. Moreover, in vitro assays provide the higher bandwidth required for optimization of early stage compounds. This proposal will 1) characterize neural oscillations in vitro in different mouse models of schizophrenia and 2) validate these new in vitro screening paradigms using well studied reference compounds in use for treatment of the positive or cognitive symptoms of schizophrenia. PUBLIC HEALTH RELEVANCE: Schizophrenia is a debilitating mental illness that affects approximately 1% of the population worldwide. The research outlined in this proposal will support the development of innovative approaches and technologies to identify new therapies for the cognitive deficits in schizophrenia, which are a major unmet medical need. This research will have a positive impact on a significant population of schizophrenia patients, their family members and caregivers. In particular, improving the cognitive outcome in patients will enhance their quality of life, enabling them to function more effectively in their personal and particularly their professional lives. This work is especially important, as the costs of unemployment due to schizophrenia have been estimated at $22 billion annually.