Constellation of HCN Channels and cAMP Regulating Proteins in Dendritic Spines of the Primate Prefrontal Cortex: Potential Substrate for Working Memory Deficits in Schizophrenia
Open accessAbstract
Schizophrenia associates with impaired prefrontal cortical (PFC) function and alterations in cyclic AMP (cAMP) signaling pathways. These include genetic insults to disrupted-in-schizophrenia (DISC1) and phosphodiesterases (PDE4s) regulating cAMP hydrolysis, and increased dopamine D1 receptor (D1R) expression that elevates cAMP. We used immunoelectron microscopy to localize DISC1, PDE4A, PDE4B, and D1R in monkey PFC and to view spatial interactions with hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that gate network inputs when opened by cAMP. Physiological interactions between PDE4s and HCN channels were tested in recordings of PFC neurons in monkeys performing a spatial working memory task. The study reveals a constellation of cAMP-related proteins (DISC1, PDE4A, and D1R) and HCN channels next to excitatory synapses and the spine neck in thin spines of superficial PFC, where working memory microcircuits interconnect and spine loss is most evident in schizophrenia. In contrast, channels in dendrites were distant from synapses and cAMP-related proteins, and were associated with endosomal trafficking. The data suggest that a cAMP signalplex is selectively positioned in the spines to gate PFC pyramidal cell microcircuits. Single-unit recordings confirmed physiological interactions between cAMP and HCN channels, consistent with gating actions. These data may explain why PFC networks are especially vulnerable to genetic insults that dysregulate cAMP signaling.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In human and rhesus monkey dlPFC, DISC1 is located in layer III spines, where it anchors PDE4A next to the spine apparatus, positioned to regulate feedforward cAMP-Ca2+ stress signaling pathways.
“Immunoelectron microscopy studies of human126 and rhesus monkey13,127 dlPFC show that DISC1 is located in layer III spines, where it anchors PDE4A next to the spine apparatus, critically positioned to regulate feedforward cAMP–Ca2+ stress signaling pathways13,127.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [127]
The ‘HCN Channels Co-Localize with cAMP Regulating Proteins in Dendritic Spines’ section reports DISC1 in monkey PFC spines and notes earlier human PFC observations. The ‘cAMP-Gated Ih Signaling in Dendritic Spines’ section places DISC1 and PDE4A near HCN channels in spines, consistent with a role in cAMP regulation. Neither passage shows that DISC1 anchors PDE4A next to the spine apparatus or establishes its role in feedforward cAMP–Ca2+ stress signaling; pages are not provided in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Stress signalling pathways that impair prefrontal cortex structure and function
Arnsten, A. F. T. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2648 · Cited by 3,299 · see citing works
Self-citationInverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory
Vijayraghavan, S., Wang, M., Birnbaum, S. G., Williams, G. V., & Arnsten, A. F. T. (2007) · Nature Neuroscience · doi:10.1038/nn1846 · Cited by 1,013 · see citing works
Self-citationWang, M., Ramos, B. P., Paspalas, C. D., Shu, Y., Simen, A., Duque, A., Vijayraghavan, S., Brennan, A., Dudley, A., Nou, E., et al. (2007) · Cell · doi:10.1016/j.cell.2007.03.015 · Cited by 672 · see citing works
Self-citationDISC1 and PDE4B Are Interacting Genetic Factors in Schizophrenia That Regulate cAMP Signaling
Millar, J. K., Pickard, B. S., Mackie, S., James, R., Christie, S., Buchanan, S. R., Malloy, M. P., Chubb, J. E., Huston, E., Baillie, G. S., et al. (2005) · Science · doi:10.1126/science.1112915 · Cited by 648 · see citing works
Dendritic Ih normalizes temporal summation in hippocampal CA1 neurons
Magee, J. C. (1999) · Nature Neuroscience · doi:10.1038/9158 · Cited by 617 · see citing works
The small pyramidal neuron of the rat cerebral cortex: The synapses upon dendritic spines
Peters, A., & Kaiserman-Abramof, I. R. (1969) · Zeitschrift f�r Zellforschung und Mikroskopische Anatomie · doi:10.1007/bf00344370 · Cited by 441 · see citing works
Hains, A. B., Vu, M. A. T., Maciejewski, P. K., van Dyck, C. H., Gottron, M., & Arnsten, A. F. T. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908563106 · Cited by 234 · see citing works
Self-citationDISC1: Structure, Function, and Therapeutic Potential for Major Mental Illness
Soares, D. C., Carlyle, B. C., Bradshaw, N. J., & Porteous, D. J. (2011) · ACS Chemical Neuroscience · doi:10.1021/cn200062k · Cited by 129 · see citing works
Taylor, J. R., Birnbaum, S., Ubriani, R., & Arnsten, A. F. T. (1999) · The Journal of Neuroscience · doi:10.1523/jneurosci.19-18-j0001.1999 · Cited by 120 · cited 2× · see citing works
“Previous work has shown that dysregulation of cAMP signaling in PFC impairs working memory (Taylor et al. 1999), and weakens network connectivity through interactions with hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (Wang et al. 2007; Arnsten et al. 2010).”
BackgroundSelf-citation
Flagged first, then by citations
Research works printed but not linked: 1
- Peters A, Palay SL, Webster HdeF. 1991. The fine structure of the nervous system: neurons and their supporting cells. New York (NY): Oxford University Press.
Cited by
Sorted by citations
Stress weakens prefrontal networks: molecular insults to higher cognition
Arnsten, A. F. T. (2015) · Nature Neuroscience · doi:10.1038/nn.4087 · Cited by 752 · see citing works
Self-citationArnsten, A. F. T., Wang, M. J., & Paspalas, C. D. (2012) · Neuron · doi:10.1016/j.neuron.2012.08.038 · Cited by 538 · see citing works
Self-citationWang, M., Yang, Y., Wang, C.-J., Gamo, N. J., Jin, L. E., Mazer, J. A., Morrison, J. H., Wang, X.-J., & Arnsten, A. F. T. (2013) · Neuron · doi:10.1016/j.neuron.2012.12.032 · Cited by 489 · see citing works
Self-citationYan, Z., & Rein, B. (2022) · Molecular Psychiatry · doi:10.1038/s41380-021-01092-3 · Cited by 300 · see citing works
“The interaction of HCN channels and cAMP regulating proteins in dendritic spines of PFC is considered to be a potential substrate of working memory [72].”
BackgroundStress-induced cognitive dysfunction: hormone-neurotransmitter interactions in the prefrontal cortex
Shansky, R. M., & Lipps, J. (2013) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2013.00123 · Cited by 205 · see citing works
“Recent work has revealed a critical role for hyperpolarization-activated/cyclic nucleotide-gated (HCN) ion channels, which co-localize on dendritic spines with D1 receptors (Paspalas et al., 2012).”
BackgroundActivity-dependent dendritic spine neck changes are correlated with synaptic strength
Araya, R., Vogels, T. P., & Yuste, R. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1321869111 · Cited by 197 · see citing works
Dopamine’s Actions in Primate Prefrontal Cortex: Challenges for Treating Cognitive Disorders
Arnsten, A. F. T., Wang, M., & Paspalas, C. D. (2015) · Pharmacological Reviews · doi:10.1124/pr.115.010512 · Cited by 149 · see citing works
Self-citationSartiani, L., Mannaioni, G., Masi, A., Novella Romanelli, M., & Cerbai, E. (2017) · Pharmacological Reviews · doi:10.1124/pr.117.014035 · Cited by 143 · see citing works
cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex
Carlyle, B. C., Nairn, A. C., Wang, M., Yang, Y., Jin, L. E., Simen, A. A., Ramos, B. P., Bordner, K. A., Craft, G. E., Davies, P., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1322360111 · Cited by 139 · see citing works
Self-citationOligomeric Aβ in the monkey brain impacts synaptic integrity and induces accelerated cortical aging
Beckman, D., Ott, S., Donis-Cox, K., Janssen, W. G., Bliss-Moreau, E., Rudebeck, P. H., Baxter, M. G., & Morrison, J. H. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1902301116 · Cited by 111 · see citing works
Psychostimulants and motivated behavior: Arousal and cognition
Berridge, C. W., & Arnsten, A. F. T. (2013) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2012.11.005 · Cited by 104 · see citing works
Self-citationGamo, N. J., Lur, G., Higley, M. J., Wang, M., Paspalas, C. D., Vijayraghavan, S., Yang, Y., Ramos, B. P., Peng, K., Kata, A., et al. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.01.009 · Cited by 97 · see citing works
Self-citationThe Neurobiology of Thought: The Groundbreaking Discoveries of Patricia Goldman-Rakic 1937-2003
Arnsten, A. F. T. (2013) · Cerebral Cortex · doi:10.1093/cercor/bht195 · Cited by 94 · see citing works
Self-citationGalvin, V. C., Yang, S. T., Paspalas, C. D., Yang, Y., Jin, L. E., Datta, D., Morozov, Y. M., Lightbourne, T. C., Lowet, A. S., Rakic, P., et al. (2020) · Neuron · doi:10.1016/j.neuron.2020.02.030 · Cited by 79 · see citing works
Self-citationThe effects of arousal on apical amplification and conscious state
Phillips, W. A., Larkum, M. E., Harley, C. W., & Silverstein, S. M. (2016) · Neuroscience of Consciousness · doi:10.1093/nc/niw015 · Cited by 75 · see citing works
Arnsten, A. F. T., Datta, D., Leslie, S., Yang, S.-T., Wang, M., & Nairn, A. C. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1903671116 · Cited by 74 · see citing works
Self-citationDatta, D., & Arnsten, A. (2019) · Brain Sciences · doi:10.3390/brainsci9050113 · Cited by 78 · see citing works
Self-citationDatta, D., Leslie, S. N., Morozov, Y. M., Duque, A., Rakic, P., van Dyck, C. H., Nairn, A. C., & Arnsten, A. F. T. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1683-1 · Cited by 76 · see citing works
Self-citationArnsten, A. F. T. (2020) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2020.107327 · Cited by 75 · see citing works
Self-citationHCN Channel Targets for Novel Antidepressant Treatment
Ku, S. M., & Han, M.-H. (2017) · Neurotherapeutics · doi:10.1007/s13311-017-0538-7 · Cited by 54 · see citing works
Arnsten, A. F. T., & Wang, M. (2016) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010715-103617 · Cited by 50 · see citing works
Self-citationNoradrenergic α1-Adrenoceptor Actions in the Primate Dorsolateral Prefrontal Cortex
Datta, D., Yang, S.-T., Galvin, V. C., Solder, J., Luo, F., Morozov, Y. M., Arellano, J., Duque, A., Rakic, P., Arnsten, A. F. T., et al. (2019) · The Journal of Neuroscience · doi:10.1523/jneurosci.2472-18.2019 · Cited by 44 · see citing works
Self-citationRole of disrupted in schizophrenia 1 (DISC1) in stress-induced prefrontal cognitive dysfunction
Gamo, N. J., Duque, A., Paspalas, C. D., Kata, A., Fine, R., Boven, L., Bryan, C., Lo, T., Anighoro, K., Bermudez, L., et al. (2013) · Translational Psychiatry · doi:10.1038/tp.2013.104 · Cited by 37 · see citing works
Self-citationFreund, N., Thompson, B. S., Sonntag, K., Meda, S., & Andersen, S. L. (2016) · Psychopharmacology · doi:10.1007/s00213-015-4200-y · Cited by 31 · see citing works
Characterization of drug binding within the HCN1 channel pore
Tanguay, J., Callahan, K. M., & D’Avanzo, N. (2019) · Scientific Reports · doi:10.1038/s41598-018-37116-2 · Cited by 29 · see citing works
Role of KCNQ potassium channels in stress-induced deficit of working memory
Arnsten, A. F. T., Jin, L. E., Gamo, N. J., Ramos, B., Paspalas, C. D., Morozov, Y. M., Kata, A., Bamford, N. S., Yeckel, M. F., Kaczmarek, L. K., et al. (2019) · Neurobiology of Stress · doi:10.1016/j.ynstr.2019.100187 · Cited by 27 · see citing works
Self-citationThe Cooperative Neuron: Cellular Foundations of Mental Life
Phillips, W. A. (2023) · doi:10.1093/oso/9780198876984.001.0001 · Cited by 13 · see citing works
- Authors
- Paspalas, C. D., Wang, M., & Arnsten, A. F. T.
- Affiliations
- Yale University (US)
- Corresponding author
- Paspalas, Constantinos D.
- Venue
- Cerebral Cortex
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-06-12
- Volume
- 23
- Issue
- 7
- Pages
- 1643-1654
- ISSN
- 1047-3211 (ISSN-L)
- 1460-2199
- PMC
- PMC3673177
- OpenAlex
- W2103131715
- Cited by
- 136
- References
- 9
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 8 · 2023: 27 · 2022: 6 · 2021: 8 · 2020: 15 · 2019: 10 · 2018: 5 · 2017: 7 · 2016: 8 · 2015: 9 · 2014: 9 · 2013: 11 · 2012: 3
- FWCI
- 4.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cerebral Cortex (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism (RL1AA017536)
- National Institute on Aging (P01AG030004)
- National Institute of Mental Health (R01MH093354)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
- Keywords
- HCN channels, cAMP signaling, dendritic spines, prefrontal cortex, schizophrenia, working memory deficits, DISC1, phosphodiesterase 4, dopamine D1 receptor, spine loss, excitatory synapses, endosomal trafficking, pyramidal neurons
- MeSH terms
- Cyclic AMP, Animals, Immunohistochemistry, Macaca mulatta, Memory Disorders, Memory, Short-Term, Schizophrenia, Microscopy, Immunoelectron, Prefrontal Cortex, Receptors, Dopamine D1, Patch-Clamp Techniques, Dendritic Spines, Cyclic Nucleotide Phosphodiesterases, Type 4, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
