The contribution of AMPA and NMDA receptors to persistent firing in the dorsolateral prefrontal cortex in working memory

Many tasks demand that information is kept online for a few seconds before it is used to guide behavior. The information is kept in working memory as the persistent firing of neurons encoding the memorized information. The neural mechanisms responsible for persistent activity are not yet well understood. Theories attribute an important role to ionotropic glutamate receptors and it has been suggested that NMDA receptors (NMDA-Rs) are particularly important for persistent firing, because they exhibit long time constants. Ionotropic AMPA receptors (AMPA-R’s) have shorter time-constants and have been suggested to play a smaller role in working memory.Here we compared the contribution of AMPA-Rs and NMDA-Rs to persistent firing in the dorsolateral prefrontal cortex (dlPFC) of male macaque monkeys performing a delayed saccade to a memorized spatial location. We used iontophoresis to eject small amounts of glutamate receptor antagonists, aiming to perturb but not abolish neuronal activity. We found that both AMPA-Rs and NMDA-Rs contributed to persistent activity. Blockers of the NMDA-Rs decreased persistent firing associated with the memory of the neuron’s preferred spatial location but had comparatively little effect on the representation of the anti-preferred location. They therefore decreased the information conveyed by persistent firing about the memorized location. In contrast, AMPA-R blockers decreased activity elicited by the memory of both the preferred and anti-preferred location, with a smaller effect on the information conveyed by persistent activity. Our results provide new insights into the contribution of AMPA-Rs and NMDA-Rs to persistent activity during working memory tasks.SIGNIFICANCE STATEMENTWorking memory enables us to hold on to information that is no longer available to the senses. It relies on the persistent activity of neurons that code for the memorized information, but the detailed mechanisms are not yet well understood. Here we investigated the role of NMDA- and AMPA-receptors in working memory using iontophoresis of antagonists in the prefrontal cortex of monkeys remembering the location of a visual stimulus for an eye movement response. AMPA- and NMDA-receptors both contributed to persistent activity. NMDA-receptor blockers mostly decreased persistent firing associated with the memory of the neuron’s preferred spatial location, whereas AMPA-receptor blockers caused a more general suppression. These results provide new insight into the contribution of AMPA- and NMDA-receptors to working memory.