Dopaminergic control of working memory and its relevance to schizophrenia: a circuit dynamics perspective

This article argues how dopamine controls working memory and how the dysregulation of the dopaminergic system is related to schizophrenia. In the dorsolateral prefrontal cortex, which is the principal part of the working memory system, recurrent excitation is subtly balanced with intracortical inhibition. A potent controller of the dorsolateral prefrontal cortical circuit is the mesocortical dopaminergic system. To understand the characteristics of the dopaminergic control of working memory, the stability of the circuit dynamics under the influence of dopamine has been studied. Recent computational studies suggest that the hyperdopaminergic state is usually stable but the hypodopaminergic state tends to be unstable. The stability also depends on the efficacy of the glutamatergic transmission in the corticomesencephalic projections to dopamine neurons. When this cortical feedback is hypoglutamatergic, the circuit of the dorsolateral prefrontal cortex tends to be unstable, such that a slight increase in dopamine releasability causes a catastrophic jump of the dorsolateral prefrontal cortex activity from a low to a high level. This may account for the seemingly paradoxical overactivation of the dorsolateral prefrontal cortex observed in schizophrenic patients. Given that dopamine transmission is abnormal in the brains of patients with schizophrenia and working memory deficit is a core dysfunction in schizophrenia, the concept of circuit stability would be useful not only for understanding the mechanisms of working memory processing but for developing therapeutic strategies to enhance cognitive functions in schizophrenia.