Cell-Type-Specific D1 Dopamine Receptor Modulation of Projection Neurons and Interneurons in the Prefrontal Cortex

Abstract

Dopamine modulation in the prefrontal cortex (PFC) mediates diverse effects on neuronal physiology and function, but the expression of dopamine receptors at subpopulations of projection neurons and interneurons remains unresolved. Here, we examine D1 receptor expression and modulation at specific cell types and layers in the mouse prelimbic PFC. We first show that D1 receptors are enriched in pyramidal cells in both layers 5 and 6, and that these cells project to intratelencephalic targets including contralateral cortex, striatum, and claustrum rather than to extratelencephalic structures. We then find that D1 receptors are also present in interneurons and enriched in superficial layer VIP-positive (VIP+) interneurons that coexpresses calretinin but absent from parvalbumin-positive (PV+) and somatostatin-positive (SOM+) interneurons. Finally, we determine that D1 receptors strongly and selectively enhance action potential firing in only a subset of these corticocortical neurons and VIP+ interneurons. Our findings define several novel subpopulations of D1+ neurons, highlighting how modulation via D1 receptors can influence both excitatory and disinhibitory microcircuits in the PFC.

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

“…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. The similar effects of D1 receptor activation that we observed support the idea that the majority of commissural fibers is targeting layer V. Furthermore, Anastasiades et al (2018) have also reported Figure 5. Effects of D1 receptor activation on PT EPSPs elicited by commissural fiber activation.…”

“…However, further exploration would be warranted to make definitive conclusions regarding the mechanism of D1R-induced burst generation. Since many commissural fibers synapse on basal dendrites of IT and PT cells within layer V (Dembrow et al, 2015;Anastasiades et al, 2018), and D1 receptors are more abundant within the deep cortical layers (Gaspar et al, 1995;Scheler and Fellous, 2001;Anastasiades et al, 2018) our data suggest that D1 receptor activation may promote burst firing initiated by enhancing basal synaptic input. Whether this effect is limited to commissural fiber activation is currently unknown, and whether the effect has any physiological significance requires further studies.…”

Sex and pubertal status influence dendritic spine density onto frontal corticostriatal projection neurons

“…While we focused on cSTR neurons, we and others have shown that cSTR neurons overlap with cortico-cortical ITtype projection neurons (Sohur et al, 2014;Winnubst et al, 2019), suggesting that our results may apply more broadly to IT-type neurons within mPFC or broader frontal cortices. On the other hand, even within mPFC significant heterogeneity has been reported among IT-type neurons (Morishima and Kawaguchi, 2006;Anastasiades et al, 2019). Consistent with previous studies, we found that dual infusion of retro-AAV into the pons and contralateral striatum labeled two intermingled but non-overlapping populations of pyramidal neurons in layer 5 of PL.…”

Cortical Foxp2 supports behavioral flexibility and developmental dopamine D1 receptor expression

“…contains Foxp2+ CThPNs and Foxp2-intratelencephalic projection neurons (ITPNs) (Sorensen et al 2015;Anastasiades et al 2018), so our result indicates that adult mouse L6 D1R+ neurons are predominantly ITPNs, and that early Foxp2 deletion causes lasting reductions in ITPN D1R expression. Because D1-like receptor density undergoes developmental pruning in PFC (Andersen et al 2000), we asked whether early postnatal CThPNs express D1R, and whether Foxp2 deletion decreases D1R in postnatal cortex.…”

“…To visualize D1R expression, we crossed our Foxp2 cKO mice with Drd1a-tdTomato reporter mice, which replicate endogenous Drd1 expression patterns in the cortex (Ade et al 2011;Anastasiades et al 2018) ( Fig. 2A).…”