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

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 cyclic adenosine monophosphate signaling, which reduces PFC neuronal firing. The current study examined whether D₁R-cyclic adenosine monophosphate 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, 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 HCN channel current, 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.