Protein kinase C overactivity impairs prefrontal cortical regulation of working memory
Abstract
The prefrontal cortex is a higher brain region that regulates thought, behavior, and emotion using representational knowledge, operations often referred to as working memory. We tested the influence of protein kinase C (PKC) intracellular signaling on prefrontal cortical cognitive function and showed that high levels of PKC activity in prefrontal cortex, as seen for example during stress exposure, markedly impair behavioral and electrophysiological measures of working memory. These data suggest that excessive PKC activation can disrupt prefrontal cortical regulation of behavior and thought, possibly contributing to signs of prefrontal cortical dysfunction such as distractibility, impaired judgment, impulsivity, and thought disorder.
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α1-Receptor stimulation impairs working memory by activating protein kinase C intracellular signaling, which is thought to be overactive in patients with bipolar disorder.
“α1-Receptor stimulation impairs working memory by activating protein kinase C intracellular signaling, which is thought to be overactive in patients with bipolar disorder (Birnbaum et al., 2004).”
From Catecholamine influences on prefrontal cortical function: Relevance to treatment of attention deficit/hyperactivity disorder and related disorders (2011) · cites this paper as Birnbaum et al., 2004
High levels of norepinephrine release, such as those encountered during a stressful condition, engage α1-receptors that suppress PFC cell firing.
“High levels of NE release, such as those encountered during a stressful condition, engage α1-receptors that suppress PFC cell firing (Birnbaum et al., 2004).”
From Catecholamine influences on prefrontal cortical function: Relevance to treatment of attention deficit/hyperactivity disorder and related disorders (2011) · cites this paper as Birnbaum et al., 2004
Studies in animals indicate that norepinephrine engages predominantly α2-receptors in the PFC when the subject is alert and interested, while actions at α1-receptors and possibly β-receptors are predominant under stressful conditions.
“Studies in animals indicate that NE engages predominantly α2-receptors in the PFC when the subject is alert and interested (Li and Mei, 1994), while actions at α1-receptors and possibly β-receptors are predominant under stressful conditions (Birnbaum et al., 2004; Ramos et al., 2005).”
From Catecholamine influences on prefrontal cortical function: Relevance to treatment of attention deficit/hyperactivity disorder and related disorders (2011) · cites this paper as Birnbaum et al., 2004
PFC function is impaired by excessive norepinephrine release.
“PFC function is also impaired by excessive NE release.”
From Catecholamine influences on prefrontal cortical function: Relevance to treatment of attention deficit/hyperactivity disorder and related disorders (2011) · cites this paper as Birnbaum et al., 2004
High levels of α1-receptor stimulation in the prefrontal cortex rapidly suppress neuronal firing and impair spatial working memory performance.
“By contrast, high levels of α1-receptor stimulation in the PFC rapidly suppress neuronal firing and impair spatial working memory performance61,62.”
From Stress signalling pathways that impair prefrontal cortex structure and function (2009) · cites this paper as [61]
Stress-induced working memory impairments can be mimicked by infusing a PKC activator into the prefrontal cortex.
“Conversely, stress-induced working memory impairments can be mimicked by infusing a PKC activator into the PFC61.”
From Stress signalling pathways that impair prefrontal cortex structure and function (2009) · cites this paper as [61]
In rodents, working memory deficits caused by pharmacological stress, cold water stress or administration of α1-agonists can be reversed by infusing PKC inhibitors directly into the prefrontal cortex.
“In rodents the working memory deficits that are caused by pharmacological stress, cold water stress or administration of α1-agonists can be reversed by infusing PKC inhibitors directly into the PFC61,88.”
From Stress signalling pathways that impair prefrontal cortex structure and function (2009) · cites this paper as [61]
Stimulation of α2A receptors increases delay-related firing of PFC neurons via inhibition of cyclic adenosine monophosphate (cAMP), while stimulation of α1 receptors decreases delay-related firing via activation of phosphatidylinositol protein kinase C signaling.
“Stimulation of α2A receptors increases delay-related firing of PFC neurons via inhibition of cyclic adenosine mono-phosphate (cAMP) (57), while stimulation of α1 receptors decreases delay-related firing via activation of phosphatidylinositol protein kinase C signaling (58).”
From Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks (2011) · cites this paper as [58]
In both rats and monkeys, stress-induced PFC dysfunction can be blocked by dopamine D1 receptor or norepinephrine α1-adrenoceptor antagonists, and conversely, it can be mimicked by high levels of D1R or α1-AR stimulation in PFC.
“In both rats and monkeys, stress-induced PFC dysfunction can be blocked by dopamine D1 receptor (D1R) or norepinephrine α1-adrenoceptor (AR) antagonists19,54, and conversely, it can be mimicked by high levels of D1R55 or α1-AR56,57 stimulation in PFC.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [57]
Inhibition of Ca2+-PKC or cAMP-PKA signaling, or blockade of HCN channels, can rescue PFC delay-cell firing and working memory functions.
“Conversely, inhibition of Ca2+–PKC or cAMP–PKA signaling, or blockade of HCN channels, can rescue PFC delay-cell firing and working memory functions57,60,62.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [57]
Norepinephrine α1-ARs activate Ca2+-protein kinase C signaling, which reduces delay-cell firing in the primate dlPFC.
“Norepinephrine α1-ARs activate Ca2+–protein kinase C (PKC) signaling, which reduces delay-cell firing in the primate dlPFC57, while high levels of dopamine D1R stimulation reduce dlPFC delay-cell firing by increasing cAMP–protein kinase A (PKA) signaling60.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [57]
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- Authors
- Birnbaum, S. G., Yuan, P. X., Wang, M., Vijayraghavan, S., Bloom, A. K., Davis, D. J., Gobeske, K. T., Sweatt, J. D., Manji, H. K., & Arnsten, A. F. T.
- Affiliations
- Baylor College of Medicine (US)
- Corresponding author
- Arnsten, A. F. T.
- Venue
- Science
- Published
- 2004-10-29
- Volume
- 306
- Issue
- 5697
- Pages
- 882-884
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2083700985
- Cited by
- 318
- References
- 18
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 8 · 2023: 7 · 2022: 10 · 2021: 26 · 2020: 8 · 2019: 16 · 2018: 14 · 2017: 14 · 2016: 12 · 2015: 15 · 2014: 16 · 2013: 19 · 2012: 15
- FWCI
- 8.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG06036)
- National Institute of Mental Health (P50MH068789)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- 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 C, prefrontal cortex, working memory, intracellular signaling, stress, cognitive impairment, distractibility, impulsivity, thought disorder, electrophysiology
- MeSH terms
- Adrenergic alpha-Agonists, Alkaloids, Animals, Carbolines, Electrophysiology, Enzyme Activation, Female, Imidazoles, Macaca mulatta, Male, Memory, Neurons, Phenanthridines, Protein Kinase C, Stress, Physiological, Tetradecanoylphorbol Acetate, Valproic Acid, Signal Transduction, Lithium Carbonate, Rats, Sprague-Dawley, Prefrontal Cortex, Receptors, Adrenergic, alpha-1, Rats, Benzophenanthridines
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