Activation of cAMP-Dependent Protein Kinase A in Prefrontal Cortex Impairs Working Memory Performance
Open accessAbstract
Activation of the adenylyl cyclase-cAMP-protein kinase A (PKA) intracellular signaling cascade is necessary for long-term memory consolidation in brain regions such as the hippocampus. However, the role of the PKA cascade in the working memory functions of the prefrontal cortex (PFC) is unknown. The present study examined the effects of manipulating PKA activity in the PFC using the cAMP stereoisomers Sp-cAMPS and Rp-cAMPS, which activate and inhibit PKA, respectively. Animals received bilateral infusions of Sp-cAMPS and/or Rp-cAMPS into the PFC immediately before testing on the delayed alternation task, a test of spatial working memory that depends on the integrity of the PFC. Low doses of Sp-cAMPS (0.21, 2. 1, or 21 nmol/0.5 microl) produced a marked, dose-dependent impairment in working memory performance. The impairment produced by infusion of Sp-cAMPS (21 nmol/0.5 microl) was fully reversed by co-infusion of Rp-cAMPS (21 nmol/0.5 microl), consistent with actions on PKA. Rp-cAMPS (21 or 42 nmol/0.5 microl) by itself had no effect on performance. These results indicate that activation of the PKA intracellular signaling cascade in the PFC impairs working memory performance. The current findings contrast with studies of long-term memory consolidation, in which inhibition of PKA with agents such as Rp-cAMPS impaired memory consolidation (Bernabeu et al., 1997; Bourtchouladze et al., 1998), whereas enhancement of the PKA pathway improved memory (Bernabeu et al., 1997; Barad et al., 1998). These results demonstrate that discrete cognitive processes subserved by different cortical regions are mediated by distinct intracellular mechanisms.
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D1 receptor activity has an inverted-U effect on working memory: both blockade and excessive stimulation impair performance, and stress causes excess dopamine release that impairs working memory via D1 signaling.
“While a lack of D1 activity can impair working memory performance, high levels of D1 stimulation also produce cognitive deficits—the classic “inverted-U” relationship.”
From Stress-induced cognitive dysfunction: hormone-neurotransmitter interactions in the prefrontal cortex (2013) · cites this paper as Taylor et al., 1999
The section “Possible relevance of PKA activation to stress-induced PFC dysfunction” reports that high D1 stimulation impairs working memory and contributes to stress-induced deficits. It does not establish that D1 blockade impairs working-memory performance, so it does not support both sides of the claimed inverted-U relationship. The section also does not explicitly say that stress causes excess dopamine release. (LLM, conf=0.84)
Experimental — accuracy not yet measuredWorking memory impairment induced by stress exposure or excessive D1 receptor stimulation can be prevented by blocking cAMP activity or HCN channels in the PFC, or mimicked by administering the cAMP analogue Sp-cAMPS.
“The impairment in working memory that is induced by stress exposure or excessive D1 receptor stimulation can be prevented by blocking cAMP activity or HCN channels in the PFC60,68 (A.F.T.A., unpublished observations) or can be mimicked by administering the cAMP analogue Sp-cAMPS96.”
From Stress signalling pathways that impair prefrontal cortex structure and function (2009) · cites this paper as [96]
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“Activation of PKA with Sp-cAMPS in the PFC impaired performance on WM tasks [62,87].”
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Self-citationA role for prefrontal calcium-sensitive protein phosphatase and kinase activities in working memory
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“blockade of cAMP-dependent protein kinase A (PKA) activity by Rp-cAMPS did not influence working memory in a delay alternation task (Taylor et al. 1999).”
MethodTrio Haploinsufficiency Causes Neurodevelopmental Disease-Associated Deficits
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“As PDE4A5 levels are reduced and PKA signaling is elevated in NEX-Trio+/ mouse cortex (Figures 7E and 7F), we treated Cre-Trio+/ neurons with Rp-cAMPS, a competitive PKA antagonist (Taylor et al., 1999).”
Klamer, D., P�lsson, E., Revesz, A., Engel, J. A., & Svensson, L. (2004) · Psychopharmacology · doi:10.1007/s00213-004-1901-z · Cited by 57 · see citing works
“There is also evidence for impaired working memory performance in rats, when increased cAMP levels are simulated in the prefrontal cortex with stereoisomeric analogues (Taylor et al. 1999).”
Torregrossa, M. M., Xie, M., & Taylor, J. R. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2012.11 · Cited by 55 · see citing works
“…has been associated with disruption of PFC-dependent tasks, and the increase in pGluR1 at the PKA site ser845 could indicate an increase in PKA activity that could be exacerbated by yohimbine to produce behavioral disruptions including greater impulsivity (Taylor et al, 1999; Arnsten et al, 2005).”
BackgroundSelf-citationCaudal, D., Godsil, B. P., Mailliet, F., Bergerot, D., & Jay, T. M. (2010) · PLoS ONE · doi:10.1371/journal.pone.0015282 · Cited by 56 · see citing works
Gilleen, J., Yakub, F., Davison, C., Kerins, S., Valdearenas, L., Uz, T., Lahu, G., Tsai, M. C., Ogrinc, F., Reichenberg, A., et al. (2018) · Psychopharmacology · doi:10.1007/s00213-018-5134-y · Cited by 53 · see citing works
Lynch, W. J., & Taylor, J. R. (2005) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2005.04305.x · Cited by 51 · see citing works
“…modulation of reward-related learning and incentive motivation have been reported following manipulation of PKA in other brain regions implicated in addiction including the basolateral amygdala (Hitchcott & Phillips, 1998; Jentsch et al., 2002) and medial prefrontal cortex (Taylor et al., 1999).”
BackgroundSelf-citationBuhot, M.-C., Wolff, M., Benhassine, N., Costet, P., Hen, R., & Ségu, L. (2003) · Learning & Memory · doi:10.1101/lm.60203 · Cited by 49 · see citing works
“In contrast, activation of the PKA pathway in the prefrontal cortex impairs delayed alternation performance (Taylor et al. 1999).”
BackgroundVandesquille, M., Baudonnat, M., Decorte, L., Louis, C., Lestage, P. J., & Béracochéa, D. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.10.006 · Cited by 46 · see citing works
Misra, K., & Pandey, S. C. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300900 · Cited by 44 · see citing works
Sun, L., Wang, X., Liu, S., Wang, Q., Wang, J., Bennecib, M., Gong, C., Sengupta, A., Grundke, I., & Iqbal, K. (2004) · FEBS Letters · doi:10.1016/j.febslet.2004.11.083 · Cited by 42 · see citing works
Distinct prefrontal molecular mechanisms for information storage lasting seconds versus minutesPreprint
Runyan, J. D., & Dash, P. K. (2005) · Learning & Memory · doi:10.1101/lm.92405 · Cited by 42 · see citing works
“Learning & Memory 235 www.learnmem.org Using a delayed alternation task, Taylor et al. (1999) demonstrated that infusion of Sp-cAMPS impairs working memory whereas Rp-cAMPS had no effect, observations consistent with the present report.”
BackgroundMethodResultInfluentialPaine, T. A., Neve, R. L., & Carlezon, W. A. (2009) · Neuropsychopharmacology · doi:10.1038/npp.2009.40 · Cited by 40 · see citing works
“…PKA activity can affect some types of cognitive performance: increased PKA activity within the mPFC impairs working memory (i.e., delays <1.0 min) (Taylor et al., 1999; Runyan and Dash, 2005) and decreased PKA activity impairs short-term memory (i.e., delays >1.5 min) (Aujula et al., 2001; Runyan…”
BackgroundMethodInfluentialBeninger, R. J., Nakonechny, P. L., & Savina, I. (2003) · Psychopharmacology · doi:10.1007/s00213-003-1510-2 · Cited by 39 · see citing works
“A similar argument might explain the observation of Taylor et al. (1999) that intra-prefrontal cortical injections of Sp-cAMPS impaired working memory performance.”
BackgroundMethodMisra, K., & Pandey, S. C. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2011.41 · Cited by 39 · see citing works
McQuail, J. A., Bañuelos, C., LaSarge, C. L., Nicolle, M. M., & Bizon, J. L. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2011.11.011 · Cited by 38 · see citing works
“While drugs directed at increasing activation of the cAMP-PKA pathway generally enhance hippocampal-dependent plasticity, disinhibiting this signaling pathway and increasing PKA activity in PFC can instead impair working memory in young adult rats (Taylor et al., 1999).”
BackgroundSenescent-induced dysregulation of cAMP/CREB signaling and correlations with cognitive decline
Hansen, R., & Zhang, H. (2013) · Brain Research · doi:10.1016/j.brainres.2013.04.033 · Cited by 37 · see citing works
HDAC Inhibition Facilitates the Switch between Memory Systems in Young But Not Aged Mice
Dagnas, M., Guillou, J., Prévot, T. D., & Mons, N. E. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.3453-12.2013 · Cited by 36 · see citing works
“The concentration was based on both published evidence in rats (Taylor et al., 1999; Ramos et al., 2003) and our recent study in C57BL/6 mice (Baudonnat et al., 2011).”
MethodPDE Inhibitors for the Treatment of Schizophrenia
Snyder, G. L., & Vanover, K. E. (2017) · Advances in neurobiology · doi:10.1007/978-3-319-58811-7_14 · Cited by 36 · see citing works
Isiegas, C., McDonough, C., Huang, T., Havekes, R., Fabian, S., Wu, L., Xu, H., Zhao, M., Kim, J., Lee, Y., et al. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.2935-07.2008 · Cited by 35 · see citing works
“However, pharmacological activation of the cAMP pathway in prefrontal cortex impairs working memory (Taylor et al., 1999).”
BackgroundNinan, I., & Wang, R. Y. (2003) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2003.02549.x · Cited by 32 · see citing works
A Central Role for Norepinephrine in the Modulation of Cerebellar Learning Tasks
Cartford, M. C., Gould, T. J., & Bickford, P. C. (2004) · Behavioral and Cognitive Neuroscience Reviews · doi:10.1177/1534582304270783 · Cited by 31 · see citing works
Sun, W., Coleman, N. T., Zelek-Molik, A., Barry, S. M., Whitfield, T. W., & McGinty, J. F. (2013) · Addiction Biology · doi:10.1111/adb.12043 · Cited by 32 · see citing works
“Increased PKA activation in the dmPFC results in abnormal working memory performance that can be rescued by Rp-cAMPs infusion (Taylor et al. 1999).”
BackgroundEl-Hassar, L., Simen, A. A., Duque, A., Patel, K. D., Kaczmarek, L. K., Arnsten, A. F. T., & Yeckel, M. F. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.12.019 · Cited by 30 · see citing works
Self-citationShansky, R., Bender, G., & Arnsten, A. (2009) · Stress · doi:10.1080/10253890802520988 · Cited by 29 · see citing works
“For example, infusion of either a D1 receptor or a cAMP agonist into the rat PFC can cause working memory deficits (Zahrt et al. 1996; Taylor et al. 1999), and the D1-mediated impairment is blocked by co-infusion of the cAMP antagonist, Rp-cAMPS.”
BackgroundSelf-citationDopamine effects on stress-induced working memory deficits
Bahari, Z., Meftahi, G. H., & Meftahi, M. A. (2018) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000429 · Cited by 27 · see citing works
“, 1997), as well as by infusions of cAMP and PKA inhibitors (Taylor et al., 1999).”
BackgroundRole 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-citationBaudonnat, M., Guillou, J., Husson, M., Vandesquille, M., Corio, M., Decorte, L., Faugère, A., Porte, Y., Mons, N. E., & David, V. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.1787-11.2011 · Cited by 26 · see citing works
“RpcAMPS can be administered intracranially to prevent brain regional CREB phosphorylation (Taylor et al., 1999; Ramos et al., 2003).”
BackgroundKlamer, D., P�lsson, E., Fejgin, K., Zhang, J., Engel, J. A., & Svensson, L. (2004) · Psychopharmacology · doi:10.1007/s00213-004-2051-z · Cited by 25 · see citing works
“Evidence also indicates impaired working memory performance in rats in response to increased cAMP levels in the prefrontal cortex simulated by stereoisomeric analogues of cAMP (Taylor et al. 1999).”
Cartford, M. C., Samec, A. M., Fister, M., & Bickford, P. C. (2004) · Learning & Memory · doi:10.1101/lm.83104 · Cited by 24 · see citing works
Kobori, N., Moore, A. N., & Dash, P. K. (2015) · Journal of Neurotrauma · doi:10.1089/neu.2014.3487 · Cited by 24 · see citing works
“on working memory performance, suggesting that either basal mPFC PKA activity does not play a role in working memory or that PKA activity is suppressed when working memory is required.(15) To”
BackgroundResultInfluentialThe effects of clozapine on delayed spatial alternation deficits in rats with hippocampal damage
Bardgett, M. E., Griffith, M. S., Foltz, R. F., Hopkins, J. A., Massie, C. M., & O’Connell, S. M. (2005) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2005.08.010 · Cited by 21 · see citing works
Hotte, M., Dauphin, F., Fréret, T., Boulouard, M., & Levallet, G. (2012) · PLoS ONE · doi:10.1371/journal.pone.0032244 · Cited by 20 · see citing works
Andrews, S. J., Das, D., Anstey, K. J., & Easteal, S. (2017) · Genes Brain & Behavior · doi:10.1111/gbb.12368 · Cited by 19 · see citing works
“The cAMP-dependent PKA signalling pathway, in turn has been shown to be involved in short- and long-term memory and working memory (Bernabeu et al. 1997; Taylor et al. 1999).”
BackgroundZhang, C.-L., Aime, M., Laheranne, É., Houbaert, X., Oussini, H. E., Martin, C., Lepleux, M., Normand, E., Chelly, J., Herzog, É., et al. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.0351-17.2017 · Cited by 19 · see citing works
“…animal performance was collected the day before, during, and the day after (Taylor et al., 1999) intra-mPFC injection of the well-tolerated PKA agonist (cAMPS-Sp, 1 g/ l) (Taylor et al., 1999), The results showed that increased PKA activity in mPFC affected not only the local network activity (Fig.”
BackgroundMethodResultInfluentialGarelick, M. G., Chan, G. C. K., DiRocco, D. P., & Storm, D. R. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.0553-09.2009 · Cited by 18 · see citing works
“For example, while increasing cAMP levels has been reported to improve hippocampus-dependent memory in aged rodents, it impairs prefrontal cortex-dependent working memory performance in young and aged rats (Taylor et al., 1999; Ramos et al., 2003).”
BackgroundWitkowski, G., Rola, R., & Szulczyk, P. J. (2012) · PubMed · Cited by 18 · see citing works
Leslie, S. N., Datta, D., Christensen, K. R., van Dyck, C. H., Arnsten, A. F. T., & Nairn, A. C. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.576723 · Cited by 17 · see citing works
“However, much of this research is based on studies of cognition linked to the hippocampus (Tibbo et al., 2019) and results may not be applicable across brain regions.”
BackgroundInfluentialSelf-citationMogensen, J., Boyd, M., Nielsen, M. D., Kristensen, R. S., & Rytter, H. M. (2008) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2008.05.005 · Cited by 17 · see citing works
Paredes, D., Cartford, M. C., Catlow, B. J., Samec, A. M., Avilas, M., George, A., Schlunck, A., Small, B. J., & Bickford, P. C. (2008) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2008.08.008 · Cited by 17 · see citing works
Phosphodiesterase as a Target for Cognition Enhancement in Schizophrenia
Al-Nema, M. Y., & Gaurav, A. (2020) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026620666200613202641 · Cited by 16 · see citing works
Baxter, M. G. (2003) · Neuron · doi:10.1016/s0896-6273(03)00715-3 · Cited by 14 · see citing works
Saha, R., Shrivastava, K., Jing, L., Schayek, R., Maroun, M., Kriebel, M., Volkmer, H., & Richter‐Levin, G. (2017) · Cerebral Cortex · doi:10.1093/cercor/bhx300 · Cited by 13 · see citing works
“Although previous reports suggest an involvement of the mPFC in working memory (Granon et al. 1994; Murphy et al. 1996; Ragozzino and Kesner 1998; Taylor et al. 1999), we did not observe working memory deficits.”
ResultRabin, B. M., Poulose, S. M., Bielinski, D. F., & Shukitt‐Hale, B. (2019) · Life Sciences in Space Research · doi:10.1016/j.lssr.2019.02.001 · Cited by 13 · see citing works
Risi, M. D., Cavezza, D., Torromino, G., Capalbo, A., Cundin, X. B., Martino, R. D., Alvino, F. G., Iemolo, A., Speranza, L., Perrone‐Capano, C., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-57788-5 · Cited by 11 · see citing works
“However, the hyperactivation of cAMP/ PKA as a consequence of D1R hyperstimulation or by direct infusion of cAMP agonists (Spc) into the mPFC 12,18,69 has been reported to impair cognition.”
Prefrontal Inositol Triphosphate Is Molecular Correlate of Working Memory in Nonhuman Primates
Lopez-Tellez, J. F., López‐Aranda, M. F., Navarro‐Lobato, I., Masmudi‐Martín, M., Martín‐Montañez, E., Blanco, E., & Khan, Z. U. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.4565-09.2010 · Cited by 11 · see citing works
“An inverse relation of WM with both cAMP (Dash et al., 2007; Wang et al., 2007) and higher PKA activity (Taylor et al., 1999) has been shown previously.”
BackgroundKaur, J., Sodhi, R. K., Madan, J., Chahal, S. K., & Kumar, R. (2017) · Pharmacological Reports · doi:10.1016/j.pharep.2017.07.009 · Cited by 11 · see citing works
Reboreda, A., Theissen, F., Valero-Aracama, M. J., Arboit, A., Corbu, M. A., & Yoshida, M. (2018) · Behavioural Brain Research · doi:10.1016/j.bbr.2018.02.042 · Cited by 11 · see citing works
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Valero-Aracama, M. J., Reboreda, A., Arboit, A., Sauvage, M. M., & Yoshida, M. (2021) · eNeuro · doi:10.1523/eneuro.0440-20.2020 · Cited by 10 · see citing works
“Interestingly, multiple studies have indicated that increased cAMP levels impair working memory, while a reduction of cAMP levels improves it (Taylor et al., 1999; Ramos et al., 2003; Runyan et al., 2005).”
BackgroundNakashima, M., Suzuki, N., Shiraishi, E., & Iwashita, H. (2019) · Behavioural Brain Research · doi:10.1016/j.bbr.2019.112192 · Cited by 9 · see citing works
The Past, Present, and Future of Phosphodiesterase-4 Modulation for Age-Induced Memory Loss
Hansen, R., & Zhang, H. (2017) · Advances in neurobiology · doi:10.1007/978-3-319-58811-7_7 · Cited by 9 · see citing works
- Authors
- Taylor, J. R., Birnbaum, S., Ubriani, R., & Arnsten, A. F. T.
- Affiliations
- Yale University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 1999-09-15
- Volume
- 19
- Issue
- 18
- Pages
- RC23-RC23
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6782445
- OpenAlex
- W1870077474
- Cited by
- 120
- References
- 27
- Citations by year
- 2025: 2 · 2022: 3 · 2021: 1 · 2020: 3 · 2019: 4 · 2018: 4 · 2017: 9 · 2016: 1 · 2015: 5 · 2014: 5 · 2013: 5 · 2012: 9
- FWCI
- 1.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Alliance for Research on Schizophrenia and Depression
- National Institute on Aging (AG06036)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- protein kinase A, prefrontal cortex, working memory, adenylate cyclase, Rp-cAMPS, delayed alternation task, spatial working memory, intracellular signaling, memory consolidation
- MeSH terms
- Cyclic AMP, Animals, Dose-Response Relationship, Drug, Enzyme Activation, Enzyme Inhibitors, Male, Memory, Short-Term, Stereoisomerism, Thionucleotides, Rats, Sprague-Dawley, Prefrontal Cortex, Cyclic AMP-Dependent Protein Kinases, Maze Learning, Rats
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