Computational Modeling of Synaptic Neurotransmission as a Tool for Assessing Dopamine Hypotheses of Schizophrenia

Abstract

Schizophrenia is a severe and complex mental disorder that causes an enormous societal and financial burden. Following the identification of dopamine as a neurotransmitter and the invention of antipsychotic drugs, the dopamine hypothesis was formulated to suggest hyperdopaminergia as the cause of schizophrenia. Over time there have been modifications and improvements to the dopamine-based model of schizophrenia, as well as models that do not implicate dopamine dysregulation as a primary cause of the disease. It seems clear by now that disruption of dopamine homeostasis occurs in schizophrenia and likely plays a major contributory role to its symptoms. Three primary versions of the dopamine hypothesis of schizophrenia have been proposed. In this article, we review these hypotheses and subject their assumptions to a computational model of dopamine signaling. Based on this review and analysis, we propose slight revisions to the existing hypotheses. Although we are still at the beginning of a comprehensive modeling effort to capture relevant phenomena associated with schizophrenia, our preliminary models have already yielded intriguing results and identified the systems biological approach as a beneficial complement to clinical and experimental research and a powerful method for exploring human diseases like schizophrenia. It is hoped that the past, present and future models will support and guide refined experimentation and lead to a deeper understanding of schizophrenia.

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