Proteomic analysis of the effects of atypical antipsychotic drugs to prevent and rescue sub chronic phencyclidine-induced cognitive deficits in rats

Schizophrenia is a disabling brain disorder that affects about 1% of Americans. Symptoms typically start between 16 and 30 years of age and rarely start after the age of 45. Available data shows that schizophrenia affects men, woman, and all ethnic groups equally. While there are some available treatments, they do not completely ameliorate the symptoms, and there are no universally effective treatments available for all affected individuals. Schizophrenia is complicated, and presents the biomedical researcher with many challenges. Unlike some genetic disorders, schizophrenia fails to show an obvious genetic cause and may be influenced by other factors such as the environment. On the economic side, shockingly, the cost of all mental illness in the US has been estimated at US$103.7 billion (1985 dollars sic), of which schizophrenia alone accounts for US$22.7 billion (1985 dollars sic). We hope that our basic research findings will boost our understanding of schizophrenia and the mechanism of atypical antipsychotics which may inform the design of more effective and specific therapeutics. Our proposal is based on of decades of successful therapeutic regimes and research with antipsychotics and aims to apply new high throughput protein analysis technologies to accelerate our understanding of schizophrenia. This proposal is based on a rodent model of schizophrenia, and we specifically document cognitive impairment of each animal with a behavior test prior to deep molecular analysis. Next, we treat the rodents with atypical antipsychotics (such as lurasidone) and later repeat the behavioral test. After documenting the results we then sacrifice the animals, extract brain tissue, and analyze the synaptic proteomes with new quantitative high throughput protein analysis tools. The approaches we aim to apply here have proven effective in multiple experimental paradigms and we expect reliable, relevant, and reproducible results in the proposed experiments. It is clear that schizophrenia represents a perplexing and at need disorder with broad and complex symptoms which could benefit from new high throughput analysis technologies. This application represents an excellent opportunity to apply new protein analysis tools to the long-standing challenge of understanding the molecular changes in schizophrenic brains and the mechanism of atypical antipsychotics. These experiments will lay the groundwork for many potential future experiments aimed on determining the neurochemical synaptic signaling mechanism perturbed in schizophrenia. Finally by repeating our behavior characterization but treating the rodents with different therapeutics we will be able to compare the specific mechanisms of drug action. The goal being to understand the differences in therapeutic action and potential to optimize drug efficacy and treatment regimens. All together we believe the discovery-based approach described in this application possess the necessary analysis power to elucidate previously inaccessible details on the molecular pathogenesis of schizophrenia.