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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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“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
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“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excessive D1 receptor stimulation can be prevented by blocking cAMP activity or HCN channels in the PFC60,68 (A.F.T.A., unpublished observations) or can be mimicked by administering the cAMP analogue Sp-cAMPS96.”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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Metadata
- 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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