Elsevier

Biological Psychiatry

Volume 78, Issue 12, 15 December 2015, Pages 860-870
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2015.01.009Get rights and content

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 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.

Section snippets

Methods and Materials

All procedures were approved by the Yale Institutional Animal Care and Use Committee.

HCN Channels and D1Rs Colocalize in Dendritic Spines of Monkey DLPFC

Dual immunoelectron microscopy revealed coexpression of D1Rs and HCN channels in pyramidal neurons, as well as spatial interaction on spine membranes in layer III monkey DLPFC. Both proteins were localized in the synthetic machinery in the soma (Figure 3A) and colocalized at the plane of the plasma membrane of dendritic spines (Figure 3B–E). Although HCN channels are prominent along the distal pyramidal dendrites, D1Rs are not present at this location (26). Thus, colocalization was found in the

Discussion

The current study showed that the impairment in PFC function during stress involves D1R opening of HCN channels to weaken PFC network connections. Combining anatomical, physiological, and behavioral evidence, we found that 1) D1Rs and HCN channels colocalize and spatially interact at dendritic spines in monkey layer III DLPFC; 2) stimulation of D1Rs increases Ih in mouse PFC slices; 3) suppression of neuronal firing by D1R-cAMP signaling can be prevented by blocking HCN channels in monkey

Acknowledgments and Disclosures

This work was supported by National Institute of Neurological Disorders and Stroke NS07224 to NJG, Public Health Service RL1AA017536 to AFTA within Consortium U54RR024350, National Alliance for Research on Schizophrenia and Depression Young Investigator Grant to YY, and National Institute of Mental Health MH099045 and a Smith Family Award for Excellence in Biomedical Research to MJH.

We thank Lisa Ciavarella, Tracy Sadlon, Sam Johnson, Michelle Wilson, and Jessica Thomas Ebbett for their

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