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.
Department of Neurobiology, Yale University, New Haven, Connecticut. Electronic address: ngamo2@jhmi.edu.
Nao J
NJ
Gamo
Department of Neurobiology, Yale University, New Haven, Connecticut; Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, New Haven, Connecticut.
Gyorgy
G
Lur
Department of Neurobiology, Yale University, New Haven, Connecticut; Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, New Haven, Connecticut.
Michael J
MJ
Higley
Department of Neurobiology, Yale University, New Haven, Connecticut.
Min
M
Wang
Department of Neurobiology, Yale University, New Haven, Connecticut.
Constantinos D
CD
Paspalas
Department of Neurobiology, Yale University, New Haven, Connecticut.
Susheel
S
Vijayraghavan
Department of Neurobiology, Yale University, New Haven, Connecticut.
Yang
Y
Yang
Department of Neurobiology, Yale University, New Haven, Connecticut.
Brian P
BP
Ramos
Department of Neurobiology, Yale University, New Haven, Connecticut.
Kathy
K
Peng
Department of Neurobiology, Yale University, New Haven, Connecticut.
Anna
A
Kata
Department of Neurobiology, Yale University, New Haven, Connecticut.
Lindsay
L
Boven
Department of Neurobiology, Yale University, New Haven, Connecticut.
Faith
F
Lin
Department of Neurobiology, Yale University, New Haven, Connecticut.
Lisette
L
Roman
Department of Neurobiology, Yale University, New Haven, Connecticut.
Daeyeol
D
Lee
Department of Neurobiology, Yale University, New Haven, Connecticut.
Amy F T
AF
Arnsten
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D049229:Dendritic Spines / Q000378:metabolism / Q000648:ultrastructure; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D008253:Macaca mulatta; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D051379:Mice; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism / Q000502:physiology*; D013312:Stress, Physiological; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure
D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D011743:Pyrimidines; D017447:Receptors, Dopamine D1; C082246:ICI D2788; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
D(1) dopamine receptor; HCN channel; Prefrontal cortex; Stress; Working memory; cAMP