Schizophrenia is a devastating mental illness that affects approximately 1% of the global population. Symptoms of schizophrenia can be grouped into three categories: positive symptoms, such as hallucinations;negative symptoms, such as social isolation and inappropriate emotional response;and cognitive symptoms. The cognitive deficits in schizophrenia include impaired attention and disruption of an essential type of short term memory called working memory. These fundamental cognitive processes are critical for performance of tasks, and their disruption in schizophrenia is a key factor underlying the inability of schizophrenia patients to function in society. Indeed the cognitive deficits in schizophrenia have been recognized as a core component of the disease. Currently available therapies for schizophrenia can ameliorate the positive symptoms, but often cause significant side effects and have not proven effective at treating the negative and cognitive symptoms of the disease. As a core feature of schizophrenia, the cognitive deficits in this disease represent a major unmet medical need. One of the challenges in discovering effective therapies for the cognitive deficits in schizophrenia has been a lack of standardized measures of the relevant cognitive processes that can be applied to evaluating drug candidates. Significant progress in defining such measures to support clinical assessment of human patients has been achieved through the NIMH Method and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative. However, there remains an urgent need to develop predictive, relevant measures in animals to support preclinical drug discovery efforts. In particular, development of predictive assays in rodents is essential, as these animal species are most applicable to early stage drug discovery. Since there is a huge gap between cognitive processes and behaviors in rodents and humans, it is challenging to identify rodent behavioral measures that map onto human cognitive domains. We are implementing a new approach to bridge this gap by directly recording the activity of brain cells (neurons) in mice during the performance of behavioral tasks. We have developed a technique to measure activity of neurons in the prefrontal cortex (PFC), a region of the brain that has been linked with the cognitive processes that are impaired in schizophrenia. Using this methodology, we have defined activities of networks of neurons in the mouse PFC that arise during states of attention. We have also observed alterations of these activities in two mouse models that bear relevance to schizophrenia. The goal of this proposal is to combine our recording technology with sophisticated mouse behavioral measures of attention and working memory. This development will permit us to directly measure the effects of candidate drugs on basic aspects of brain activity that are relevant to these behaviors. We believe that this advance will provide the urgently needed animal measures for predicting efficacy of cognitive therapies in humans. The research outlined in this proposal will directly benefit the large population of schizophrenia patients and their families by supporting the discovery of new, more effective therapies. This proposal also supports the mission of economic stimulus by providing jobs and supporting equipment purchases. The research outlined in this proposal will support the identification of new therapies for the cognitive deficits in schizophrenia, which are a major unmet medical need. This research will thus have a positive impact on the significant population of schizophrenia patients and their family members and caregivers, which includes many millions of people worldwide. In particular, improving the cognitive outcome in schizophrenia will help patients to improve their job performance and to integrate into society more effectively.
The research outlined in this proposal will support the identification of new therapies for the cognitive deficits in schizophrenia, which are a major unmet medical need. This research will thus have a positive impact on the significant population of schizophrenia patients and their family members and caregivers, which includes many millions of people worldwide. In particular, improving the cognitive outcome in schizophrenia will help patients to improve their job performance and to integrate into society more effectively.
| Cottrell, Jeffrey R; Levenson, Jonathan M; Kim, Sung Hyun et al. (2013) Working memory impairment in calcineurin knock-out mice is associated with alterations in synaptic vesicle cycling and disruption of high-frequency synaptic and network activity in prefrontal cortex. J Neurosci 33:10938-49 |
