Under the curve: critical issues for elucidating D1 receptor function in working memory

It has been postulated that spatial working memory operates optimally within a limited range of dopamine transmission and D1 dopamine receptor signaling in prefrontal cortex. Insufficiency in prefrontal dopamine, as in aging, and excessive transmission, as in acute stress, lead to impairments in working memory that can be ameliorated by D1 receptor agonist and antagonist treatment, respectively. Iontophoretic investigations of dopamine's influence on the cellular mechanisms of working memory have revealed that moderate D1 blockade can enhance memory fields in primate prefrontal pyramidal neurons while strong blockade abolishes them. The combined behavioral and physiological evidence indicates that there is a normal range of dopamine function in prefrontal cortex that can be described as an "inverted-U" relationship between dopamine transmission and the integrity of working memory. Both in vivo and in vitro studies have demonstrated a role for dopamine in promoting the excitability of prefrontal pyramidal cells and facilitating their N-methyl-d-aspartate inputs, while simultaneously restraining recurrent excitation and facilitating feedforward inhibition. This evidence indicates that there is a fine balance between the synergistic mechanisms of D1 modulation in working memory. Given the critical role of prefrontal function for cognition, it is not surprising that this balancing act is perturbed by both subtle genetic influences and environmental events. Further, there is evidence for an imbalance in these dopaminergic mechanisms in multiple neuropsychiatric disorders, particularly schizophrenia, and in related nonhuman primate models. Elucidating the orchestration of dopamine signaling in key nodes within prefrontal microcircuitry is therefore pivotal for understanding the influence of dopamine transmission on the dynamics of working memory. Here, we explore the hypothesis that the window of optimal dopamine signaling changes on a behavioral time-scale, dependent upon current cognitive demands and local neuronal activity as well as long-term alterations in signaling pathways and gene expression. If we look under the bell-shaped curve of prefrontal dopamine function, it is the relationship between neuromodulation and cognitive function that promises to bridge our knowledge between molecule and mind.