Synaptic Activity Unmasks Dopamine D2 Receptor Modulation of a Specific Class of Layer V Pyramidal Neurons in Prefrontal Cortex

Abstract

Dopamine D2 receptors (D2Rs) play a major role in the function of the prefrontal cortex (PFC), and may contribute to prefrontal dysfunction in conditions such as schizophrenia. Here we report that in mouse PFC, D2Rs are selectively expressed by a subtype of layer V pyramidal neurons that have thick apical tufts, prominent h-current, and subcortical projections. Within this subpopulation, the D2R agonist quinpirole elicits a novel afterdepolarization that generates voltage fluctuations and spiking for hundreds of milliseconds. Surprisingly, this afterdepolarization is masked in quiescent brain slices, but is readily unmasked by physiologic levels of synaptic input which activate NMDA receptors, possibly explaining why this phenomenon has not been reported previously. Notably, we could still elicit this afterdepolarization for some time after the cessation of synaptic stimulation. Besides NMDA receptors, the quinpirole-induced afterdepolarization also depended on L-type Ca2+ channels and was blocked by selective L-type antagonist nimodipine. To confirm that D2Rs can elicit this afterdepolarization by enhancing Ca2+ (and Ca2+-dependent) currents, we measured whole-cell Ca2+ potentials that occur after blocking Na+ and K+ channels, and found quinpirole enhanced these potentials, while the selective D2R antagonist (−)sulpiride had the opposite effect. Thus, D2Rs can elicit a Ca2+-channel dependent afterdepolarization that powerfully modulates activity in specific prefrontal neurons. Through this mechanism, D2Rs might enhance outputs to subcortical structures, contribute to reward related persistent firing, or increase the level of noise in prefrontal circuits.

D3 Receptors Regulate Excitability in a Unique Class of Prefrontal Pyramidal Cells

“…D3ϩ cells were further distinguished from D2ϩ cells by their axonal projection targets. Although D2ϩ, Type 2 neurons targeted subcortical regions such as the pons and thalamus, D3ϩ neurons had projection patterns more consistent with D1ϩ neurons, including projections to contralateral mPFC and bilateral NAcc and BLA (Dembrow et al, 2010;Gee et al, 2012;Seong and Carter, 2012;Land et al, 2014). Based on these results, we propose that D1R, D2R, and D3R expression defines largely distinct L5 pyramidal cell classes in mPFC, each with unique catecholaminergic responses.…”

“…influence resting membrane properties (Dembrow et al, 2010;Gee et al, 2012;Seong and Carter, 2012). We found that D1ϩ, D2ϩ, and D3ϩ neurons had different input resistances when subjected to a Ϫ50 pA current pulse (D1ϩ: 183 Ϯ 5 M⍀, n ϭ 95; D2ϩ: 146 Ϯ 11 M⍀, n ϭ 35; D3ϩ: 212 Ϯ 5 M⍀, n ϭ 188; Kruskal-Wallis, H (2) ϭ 32.91, p ϭ 7 ϫ 10 Ϫ8 ; Wilcoxon's ranksum test, Holm-Sidak correction, D1ϩ vs D2ϩ: z ϭ 3.75, D1ϩ vs D3ϩ: z ϭ Ϫ3.32, D2ϩ vs D3ϩ: z ϭ Ϫ5.01; p Ͻ 0.05) and that D2ϩ cell resting V m was modestly depolarized relative to D3ϩ cells (D1ϩ: Ϫ80.0 Ϯ 0.6 mV; D2ϩ: Ϫ77.9 Ϯ 0.7 mV; D3ϩ: Ϫ80.2 Ϯ 0.4 mV; Kruskal-Wallis, H (2) ϭ 7.26, p ϭ 0.027; Wilcoxon's rank-sum test, Holm-Sidak correction, D2ϩ vs D3ϩ: z ϭ 2.76; p Ͻ 0.05; Fig.…”

Prefrontal Dopamine D1 and D2 Receptors Regulate Dissociable Aspects of Decision Making via Distinct Ventral Striatal and Amygdalar Circuits

“…A potential answer comes from neuroanatomical studies that have identified separate populations of PFC pyramidal neurons that only express D 1 or D 2 receptors, with relatively few neurons expressing both (Vincent et al, 1993;Gaspar et al, 1995;Santana et al, 2009). Moreover, D 1 -versus D 2 -expressing cells display distinct neurophysiological properties and, in some instances, different subcortical projection targets (Gaspar et al, 1995;Gee et al, 2012;Seong and Carter, 2012). This neuroanatomical framework leaves open the possibility that mesocortical DA may act on separate networks of neurons that are modulated by D 1 or D 2 receptor activity.…”

Dopamine D2 Receptors Modulate Pyramidal Neurons in Mouse Medial Prefrontal Cortex through a Stimulatory G-Protein Pathway

“…Specifically, we found that D2Rs are selectively expressed within thick-tufted, subcortically projecting (SC) L5 pyramidal neurons, which exhibit prominent hyperpolarization-activated cationic current (I h ) (Gee et al, 2012). We found that, in this population, pharmacological activation of D2Rs by the agonist quinpirole elicits a profound afterdepolarization (ADP) following depolarizing current injection.…”

“…Recently, our laboratory and others have shown that, in the mouse mPFC, three major subtypes of dopamine receptors (D1Rs, D2Rs, and D3Rs) are differentially expressed by distinct subtypes of layer 5 (L5) pyramidal neurons (Gee et al, 2012;Seong and Carter, 2012;Clarkson et al, 2017). Specifically, we found that D2Rs are selectively expressed within thick-tufted, subcortically projecting (SC) L5 pyramidal neurons, which exhibit prominent hyperpolarization-activated cationic current (I h ) (Gee et al, 2012).…”