The roles of NMDA- and GABA receptors for working memory activity in primate prefrontal cortex

Abstract

The persistent activation of prefrontal neurons after a stimulus has disappeared is considered a neuronal correlate of working memory. Current explanations suggest that persistent activation during a delay depends on a delicate but poorly understood interplay between excitatory glutamatergic and inhibitory GABAergic receptor effects. We addressed the roles of these receptor systems directly by iontophoretically applying the NMDA receptor antagonist MK-801 and the GABA(A) receptor antagonist bicuculline methiodide while simultaneously recording extracellular activity in prefrontal cortex of monkeys performing a working memory task. Following a delay period monkeys had to decide whether they had previously seen a stimulus that was either absent or present at intensities close to perceptual threshold. The blockade of GABA(A) receptors strongly improved the stimulus selectivity of the neurons’ delay activity, causing an increase in signal to noise ratio during working memory periods as well as an enhancement of the neurons’ coding selectivity. The blockade of NMDA receptors resulted in a slight enhancement of stimulus selectivity and encoding capacity of the neurons. Inactivation of both NMDA- and GABA(A) receptors in the same individual neurons showed a similar enhancement of the neurons’ coding selectivity. Our findings emphasize the delicate and more complex than expected interplay of excitatory and inhibitory transmitter systems in modulating working memory coding in prefrontal circuits.