Stress Impairs Prefrontal Cortical Function via D1 Dopamine Receptor Interactions With Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels

Abstract

Background Psychiatric disorders such as schizophrenia are worsened by stress, and working memory deficits are often a central feature of illness. Working memory is mediated by the persistent firing of prefrontal cortical (PFC) pyramidal neurons. Stress impairs working memory via high levels of dopamine D1 receptor (D1R) activation of cAMP signaling, which reduces PFC neuronal firing. The current study examined whether D1R-cAMP signaling reduces neuronal firing and impairs working memory by increasing the open state of hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels, which are concentrated on dendritic spines where PFC pyramidal neurons interconnect. Methods A variety of methods were employed to test this hypothesis: dual immunoelectron microscopy localized D1R and HCN channels, in vitro recordings tested for D1R actions on HCN channel current (Ih), while recordings in monkeys performing a working memory task tested for D1R-HCN channel interactions in vivo. Finally, cognitive assessments following intra-PFC infusions of drugs examined D1R-HCN channel interactions on working memory performance. Results Immunoelectron microscopy confirmed D1R colocalization with HCN channels near excitatory-like synapses on dendritic spines in primate PFC. Mouse PFC slice recordings demonstrated that D1R stimulation increased Ih, while local HCN channel blockade in primate PFC protected task-related firing from D1R-mediated suppression. D1R stimulation in rat or monkey PFC impaired working memory performance, while HCN channel blockade in PFC prevented this impairment in rats exposed to either stress or D1R stimulation. Conclusions These findings suggest that D1R stimulation or stress weakens PFC function via opening of HCN channels at network synapses.

Dopamine’s Actions in Primate Prefrontal Cortex: Challenges for Treating Cognitive Disorders

“…These channels are opened by cAMP and protein kinase A, respectively, weakening the efficacy of synaptic connections and reducing neuronal firing . As described below, D1R in spines are also localized near this complex, e.g., next to HCN channels and the synapse Gamo et al, 2015), and Delay cells are powerfully modulated by D1/5R but not D2/3R stimulation (Wang et al, 2004).…”

“…The reduction in firing to nonpreferred inputs may include 1) increased opening of HCN and KCNQ channels on spines, 2) a reduction in glutamate release from axon terminals as has been seen in ferret (Gao et al, 2001), and 3) facilitation of the lateral inhibition provided by GABAergic interneurons. D1R in spines are typically found next to glutamate-like synapses, where they are colocalized with HCN channels Gamo et al, 2015) (Fig. 3A).…”

“…However, it was soon discovered that high doses of D1/5R agonists, or very high levels of DA release in PFC, as occurs during stress exposure, could be as detrimental to cognitive function as DA depletion, and the detrimental effects of stress involved excessive stimulation of D1/5R Goldman-Rakic, 1990, 1998;Murphy et al, 1996). The administration of D1/5R-selective agonists (SKF38393 [1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol], SKF81297 [(6)-6-chloro-2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine], A77636 [1R-cis-1-(aminomethyl)-3,4-dihydro-3-tricyclo[3.3.1.13,7] dec-1-yl-[1H]-2-benzopyran-5,6-diol]) revealed an inverted U-shaped dose response, where either high-dose D1/5R antagonist or D1/5R agonist treatment impaired performance after systemic or intra-PFC infusions, whereas low doses of agonist improved performance, especially in monkeys with DA depletion (Arnsten et al, 1994; Prefrontal Dopamine and Cognitive Disorders Cai and Arnsten, 1997;Zahrt et al, 1997;Gamo et al, 2015). Later studies found parallel, inverted U-shaped influences on dlPFC neuronal physiology (Williams and Goldman-Rakic, 1995;Vijayraghavan et al, 2007;Arnsten et al, 2009), as described in detail below.…”

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

“…When the complex forms, for instance, the quaternary structure could display novel specific allosteric sites (Agnati et al, 2008). Furthermore, RM are in the center of two complementary networks of interactions: HMN involving (A) the lipid environment (Gahbauer and Böckmann, 2016), (B) RAMP (Foord and Marshall, 1999), (C) RTK , and (D) membrane channels (Liu et al, 2006a;Gamo et al, 2015) and VMN leading to (E) modulation of the binding sites (Fuxe et al, 1998), (F) modulation of G protein activation (Ferrada et al, 2009), (G) modulation of the signaling cascade, among others, and (H) switching from G protein to β-arrestin signaling (Rashid et al, 2007;Rozenfeld et al, 2012).…”

“…In fact, D 1 receptors and HCN colocalize in layer III of dorsolateral prefrontal cortex and the suppression of neuronal firing by D 1 signaling can be prevented by blocking HCN channels. Correspondently, working memory impairment induced by D 1 stimulation or pharmacologic stress can be prevented by blocking HCN channels in the rat prefrontal cortex (Gamo et al, 2015).…”