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.
Keywords
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Article info
Publication history
Published online: February 04, 2015
Accepted:
January 22,
2015
Received in revised form:
January 19,
2015
Received:
July 30,
2014
Identification
Copyright
© 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
