Layer-specific effects of dopaminergic D1 receptor activation on excitatory synaptic trains in layer V mouse...

In humans, executive functions (e.g., working memory [WM]) are mediated in part by prefrontal cortical areas (PFC), where ventromedial areas may be homologous to ventromedial areas (mPFC) in rodents. Many executive functions are critically dependent on optimal dopamine levels within the PFC; however, our understanding of the role of dopamine in modulating PFC-mediated tasks is incomplete. Stable patterns of neuronal activity have been associated with WM processes, and recurrent excitatory synaptic activity has been proposed to play a role in this sustained activity. This excitatory activity may be regulated in a frequency-dependent manner. Thus, we examined the effects of dopamine D1-like receptor (D1R) activation on short-term excitatory postsynaptic potential (EPSP) dynamics in two subtypes of mouse layer V mPFC pyramidal neurons by varying evoked train frequency from 10 to 50 Hz. We isolated non-NMDA receptor (non-NMDAR) and NMDA receptor (NMDAR)-mediated components of EPSP trains, which were evoked by stimulating fibers located either within layer V or layer I of the mPFC. Interestingly, no differences in the effects of D1R activation were observed between subcortically projecting (PT or pyramidal tract) and contralaterally projecting (IT or intratelencephalic) layer V pyramidal cells. However, we found that D1R activation had layer-specific effects on NMDAR- and non-NMDAR-mediated EPSP trains: while D1R activation increased the amplitude of both components with layer V stimulation, with layer I stimulation D1R activation had no effect on non-NMDAR-mediated EPSP trains but decreased the amplitude of NMDAR-mediated EPSP trains. Our results suggest that dopamine, acting at D1-like receptors, increases the influence of local inputs from other layer V pyramidal cells, but may restrict the influence of layer I (tuft) inputs. Our demonstration of differential D1R regulation of excitatory synaptic dynamics in distinct compartments of mPFC layer V neurons may provide another important aspect linking cellular mechanisms of dopaminergic modulation to PFC network functioning, and ultimately to executive functions such as working memory.