Dopamine Increases Inhibition in the Monkey Dorsolateral Prefrontal Cortex through Cell Type-Specific Modulation of Interneurons

Abstract

Dopaminergic modulation of the dorsolateral prefrontal cortex (DLPFC) plays an important role in cognitive functions, including working memory. At optimal concentrations, dopamine (DA) enhances pyramidal cell (PC) firing to increase task-related activity. However, spatial and temporal "tuning" of the persistent firing that underlies this mnemonic activity requires inhibitory control from gamma-aminobutyric acidergic (GABAergic) interneurons. How DA modulates the inhibitory control provided by different types of interneurons in the primate cortex is not known. We studied the effects of DA and DA receptor-specific agonists and antagonists on GABAergic inhibition and interneuron excitability in slices from primate DLPFC. Using whole-cell voltage-clamp recordings from layer 2/3 pyramidal neurons, we examined the effects of DA on spontaneous (action potential dependent) and miniature (action potential independent) inhibitory postsynaptic currents. We found that DA can increase inhibition via a presynaptic, action potential-dependent mechanism. In current-clamp recordings from physiologically and morphologically identified interneurons, we investigated the pharmacology and cell type specificity of this effect. DA increased the excitability of fast-spiking (FS), nonadapting interneurons via activation of D1- but not D2-type receptors. In contrast, DA had no effect on interneurons with adapting firing patterns. Thus, DA and D1 receptor activation affect local recurrent circuits by selectively modulating FS interneurons that control the firing of PCs through perisomatic innervation.