Role of dopamine receptors in working memory capacity

Working memory capacity (WMC) is the limited number of elements that we can remember for a short retention interval, which is about 6 objects in humans and mice. D1-like agonists regulate WMC according to a “U-shaped” dose-response. In this study, we tested the hypothesis that D1-like agonists expand WMC in normal mice by a different pattern of activation of cAMP-dependent Protein Kinase (PKA) in the striatum. WMC was evaluated by the different-identical objects task/DOT-IOT for mice. The effects of systemic injection of the D1-like agonists on WMC and PKA activity were evaluated through western blot analysis on striatal and frontal tissue. The role of PKA activation in mediating WMC was evaluated by focal brain injection of the agonist and the antagonist and by chemogenetic approaches (DREADDs). Low doses of D1-like agonists increased WMC from 6 to 8 objects. Surprisingly, the improvement was mediated by the activation of PKA within the striatum. These findings show for the first time that pharmacological activation of striatal DA D1-PKA pathway activation expands WMC beyond its natural limit. Furthermore, they show that increasing doses of D1 agonist impairs WMC by concurrently activating PKA in the frontal cortex. These data suggest the first post-synaptic mechanism explainingwhythe WM improvement effects of D1 agonistsfollow an “inverted U-shaped”dose-response curve.