Dopamine D1 and D5 receptors are localized to discrete populations of interneurons in primate prefrontal cortex

Abstract

Working memory (WM) is a core cognitive process that depends upon activation of D1 family receptors (D1R) and inhibitory interneurons in the prefrontal cortex (PFC). D1R are comprised of the D1 and D5 subtypes, and D5 has a 10-fold higher affinity for dopamine. Parvalbumin (PV) and calretinin (CR) are 2 interneuron populations that are differentially affected by D1R stimulation and have discrete postsynaptic targets, such that PV interneurons provide strong inhibition to pyramidal cells, whereas CR interneurons inhibit other interneurons. The distinct properties of both the D1R and interneuron subtypes may contribute to the "inverted-U" relationship of D1R stimulation and WM ability. To determine the prevalence of D1 and D5 in PV and CR interneurons, we performed quantitative double-label immunoelectron microscopy in layer III of macaque area 9. We found that D1 was the predominant D1R subtype in PV interneurons and was found mainly in dendrites. In contrast, D5 was the predominant D1R subtype in CR interneurons and was found mainly in dendrites. Integrating these findings with previously published electrophysiological data, we propose a circuitry model as a framework for understanding the inverted-U relationship between dopamine stimulation of D1R and WM performance.