Layer-specific effects of dopaminergic D1 receptor activation on excitatory synaptic trains in layer V mouse prefrontal cortical pyramidal cells

Abstract

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.

Dopaminergic D1 receptor effects on commissural inputs targeting layer V pyramidal subtypes of the mouse medial prefrontal cortex

“…Regarding the effects of D1 receptor activation, our current results are in line with results from our previous study (Leyrer-Jackson and Thomas, 2018). As reported here, D1 receptor activation increased the amplitude of EPSPs evoked in both subtypes of layer V pyramidal cells by direct layer V stimulation.…”

“…Finally, in a previous study, we used local stimulation of layer V to characterize evoked EPSP trains in layer V pyramidal cells (Leyrer‐Jackson and Thomas, ; Leyrer‐Jackson and Thomas, ). In contrast to the present study, the majority of axonal fibers activated by direct stimulation of layer V is comprised of a mixture of PT and IT axons, and the evoked EPSPs showed a mixture of facilitating and depressing responses that was not correlated with postsynaptic cell type.…”

“…While not significant, we report that bursting PT cells show longer EPSP decay time constants compared to nonbursting PT cells. Thus, D1 receptor activation may promote bursting in a subset of PT cells by enhancing NMDA receptor activation in basal dendrites (Leyrer‐Jackson and Thomas, ) and conceivably, NMDA spikes (Vincent et al, ). However, further exploration would be warranted to make definitive conclusions regarding the mechanism of D1R‐induced burst generation.…”

“…However, the modulatory effects of dopaminergic receptor activation on these synaptic dynamics are unknown. In previous studies, we demonstrated that dopamine has cell compartment and receptor subtype-specific effects on excitatory transmission in mPFC layer V cells (Leyrer-Jackson and Thomas, 2017;Leyrer-Jackson and Thomas, 2018). In the current study, we used optogenetic techniques to characterize the effects of D1 receptor activation on short-term synaptic dynamics of commissural inputs into both subtypes of layer V pyramidal neurons.…”

Drugs of Abuse Differentially Alter the Neuronal Excitability of Prefrontal Layer V Pyramidal Cell Subtypes

“…Lastly, we explored potential differences in these measurements between type I and type II pyramidal cells, which were distinguished based on the presence of a prominent “sag” in response to a 125 pA hyperpolarizing current, and by initial firing of doublets (found in type I cells only). Both criteria for cell type identification have been used in previous studies ( Dembrow et al, 2010 ; Spindle and Thomas, 2014 ; Leyrer-Jackson and Thomas, 2018 ).…”