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

Nao J. Gamo, Gyorgy Lur, Michael J. Higley, Min Wang, Constantinos D. Paspalas, Susheel Vijayraghavan, Yang Yang, Brian P. Ramos, Kathy Peng, Anna Kata, Lindsay Boven, Faith Lin, Lisette Roman, Daeyeol Lee, Amy F.T. Arnsten

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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.

Original languageEnglish (US)
Pages (from-to)860-870
Number of pages11
JournalBiological Psychiatry
Volume78
Issue number12
DOIs
StatePublished - Dec 15 2015

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Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
Dopamine D1 Receptors
Short-Term Memory
Dendritic Spines
Immunoelectron Microscopy
Pyramidal Cells
Cyclic AMP
Synapses
Primates
Haplorhini
Cyclic Nucleotide-Gated Cation Channels
Memory Disorders
Psychiatry
Schizophrenia

All Science Journal Classification (ASJC) codes

  • Biological Psychiatry

Cite this

Gamo, Nao J. ; Lur, Gyorgy ; Higley, Michael J. ; Wang, Min ; Paspalas, Constantinos D. ; Vijayraghavan, Susheel ; Yang, Yang ; Ramos, Brian P. ; Peng, Kathy ; Kata, Anna ; Boven, Lindsay ; Lin, Faith ; Roman, Lisette ; Lee, Daeyeol ; Arnsten, Amy F.T. / Stress Impairs Prefrontal Cortical Function via D1 Dopamine Receptor Interactions with Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels. In: Biological Psychiatry. 2015 ; Vol. 78, No. 12. pp. 860-870.
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title = "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 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.",
author = "Gamo, {Nao J.} and Gyorgy Lur and Higley, {Michael J.} and Min Wang and Paspalas, {Constantinos D.} and Susheel Vijayraghavan and Yang Yang and Ramos, {Brian P.} and Kathy Peng and Anna Kata and Lindsay Boven and Faith Lin and Lisette Roman and Daeyeol Lee and Arnsten, {Amy F.T.}",
year = "2015",
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Gamo, NJ, Lur, G, Higley, MJ, Wang, M, Paspalas, CD, Vijayraghavan, S, Yang, Y, Ramos, BP, Peng, K, Kata, A, Boven, L, Lin, F, Roman, L, Lee, D & Arnsten, AFT 2015, 'Stress Impairs Prefrontal Cortical Function via D1 Dopamine Receptor Interactions with Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels', Biological Psychiatry, vol. 78, no. 12, pp. 860-870. https://doi.org/10.1016/j.biopsych.2015.01.009

Stress Impairs Prefrontal Cortical Function via D1 Dopamine Receptor Interactions with Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels. / Gamo, Nao J.; Lur, Gyorgy; Higley, Michael J.; Wang, Min; Paspalas, Constantinos D.; Vijayraghavan, Susheel; Yang, Yang; Ramos, Brian P.; Peng, Kathy; Kata, Anna; Boven, Lindsay; Lin, Faith; Roman, Lisette; Lee, Daeyeol; Arnsten, Amy F.T.

In: Biological Psychiatry, Vol. 78, No. 12, 15.12.2015, p. 860-870.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Stress Impairs Prefrontal Cortical Function via D1 Dopamine Receptor Interactions with Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels

AU - Gamo, Nao J.

AU - Lur, Gyorgy

AU - Higley, Michael J.

AU - Wang, Min

AU - Paspalas, Constantinos D.

AU - Vijayraghavan, Susheel

AU - Yang, Yang

AU - Ramos, Brian P.

AU - Peng, Kathy

AU - Kata, Anna

AU - Boven, Lindsay

AU - Lin, Faith

AU - Roman, Lisette

AU - Lee, Daeyeol

AU - Arnsten, Amy F.T.

PY - 2015/12/15

Y1 - 2015/12/15

N2 - 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.

AB - 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.

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U2 - 10.1016/j.biopsych.2015.01.009

DO - 10.1016/j.biopsych.2015.01.009

M3 - Article

C2 - 25731884

AN - SCOPUS:84942452285

VL - 78

SP - 860

EP - 870

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

IS - 12

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