Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

Science 306 (5697): 882-884

Copyright © 2004 by the American Association for the Advancement of Science

Protein Kinase C Overactivity Impairs Prefrontal Cortical Regulation of Working Memory

S. G. Birnbaum,1,2 P. X. Yuan,3 M. Wang,1 S. Vijayraghavan,1 A. K. Bloom,1 D. J. Davis,1 K. T. Gobeske,1 J. D. Sweatt,2 H. K. Manji,3 A. F. T. Arnsten1*

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.

1 Department of Neurobiology, Yale Medical School, 333 Cedar Street, New Haven, CT 06520–8001, USA.
2 Department of Neuroscience, 1 Baylor Plaza, Baylor College of Medicine, Houston TX 77030, USA.
3 Laboratory of Molecular Pathophysiology, National Institute of Mental Health (NIMH), Bethesda, MD 20892–4405, USA.

* To whom correspondence should be addressed. E-mail: amy.arnsten{at}yale.edu

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Catecholamine receptors differentially mediate impulsive choice in the medial prefrontal and orbitofrontal cortex.
M. C. Pardey, N. N. Kumar, A. K. Goodchild, and J. L. Cornish (2013)
J Psychopharmacol 27, 203-212
   Abstract »    Full Text »    PDF »
Bezafibrate administration improves behavioral deficits and tau pathology in P301S mice.
M. Dumont, C. Stack, C. Elipenahli, S. Jainuddin, M. Gerges, N. Starkova, N. Y. Calingasan, L. Yang, D. Tampellini, A. A. Starkov, et al. (2012)
Hum. Mol. Genet. 21, 5091-5105
   Abstract »    Full Text »    PDF »
Task demands dissociate the effects of muscarinic M1 receptor blockade and protein kinase C inhibition on attentional performance in rats.
A. M. Robinson, D. F. Mangini, and J. A. Burk (2012)
J Psychopharmacol 26, 1143-1150
   Abstract »    Full Text »    PDF »
Comparative Lipidomic Analysis of Mouse and Human Brain with Alzheimer Disease.
R. B. Chan, T. G. Oliveira, E. P. Cortes, L. S. Honig, K. E. Duff, S. A. Small, M. R. Wenk, G. Shui, and G. Di Paolo (2012)
J. Biol. Chem. 287, 2678-2688
   Abstract »    Full Text »    PDF »
Time-dependent corticosteroid modulation of prefrontal working memory processing.
M. J. A. G. Henckens, G. A. van Wingen, M. Joels, and G. Fernandez (2011)
PNAS 108, 5801-5806
   Abstract »    Full Text »    PDF »
Effects of modafinil and prazosin on cognitive and physiological functions in healthy volunteers.
S. Winder-Rhodes, S. Chamberlain, M. Idris, T. Robbins, B. Sahakian, and U. Muller (2010)
J Psychopharmacol 24, 1649-1657
   Abstract »    PDF »
Coincidence Detection and Stress Modulation of Spike Time-Dependent Long-Term Depression in the Hippocampus.
P. Niehusmann, G. Seifert, K. Clark, H. C. Atas, I. Herpfer, B. Fiebich, J. Bischofberger, and C. Normann (2010)
J. Neurosci. 30, 6225-6235
   Abstract »    Full Text »    PDF »
A role for PKC in mediating stress-induced prefrontal cortical structural plasticity and cognitive function.
G. Chen, I. D. Henter, and H. K. Manji (2009)
PNAS 106, 17613-17614
   Full Text »    PDF »
Inhibition of protein kinase C signaling protects prefrontal cortex dendritic spines and cognition from the effects of chronic stress.
A. B. Hains, M. A. T. Vu, P. K. Maciejewski, C. H. van Dyck, M. Gottron, and A. F. T. Arnsten (2009)
PNAS 106, 17957-17962
   Abstract »    Full Text »    PDF »
Prenatal Cocaine Reduces AMPA Receptor Synaptic Expression through Hyperphosphorylation of the Synaptic Anchoring Protein GRIP.
K. Bakshi, S. Gennaro, C. Y. Chan, M. Kosciuk, J. Liu, A. Stucky, E. Trenkner, E. Friedman, R. G. Nagele, and H.-Y. Wang (2009)
J. Neurosci. 29, 6308-6319
   Abstract »    Full Text »    PDF »
Severe Psychological Stress in Elderly Individuals: A Proposed Model of Neurodegeneration and Its Implications.
M. Tsolaki, F. Kounti, and S. Karamavrou (2009)
American Journal of Alzheimer's Disease and Other Dementias 24, 85-94
   Abstract »    PDF »
Molecular mechanisms of stress-induced prefrontal cortical impairment: Implications for mental illness.
A. B. Hains and A. F.T. Arnsten (2008)
Learn. Mem. 15, 551-564
   Abstract »    Full Text »    PDF »
Blockade of IP3-mediated SK channel signaling in the rat medial prefrontal cortex improves spatial working memory.
A. R. Brennan, B. Dolinsky, M.-A. T. Vu, M. Stanley, M. F. Yeckel, and A. F.T. Arnsten (2008)
Learn. Mem. 15, 93-96
   Abstract »    Full Text »    PDF »
Prefrontal cortex and hippocampus subserve different components of working memory in rats.
T. Yoon, J. Okada, M. W. Jung, and J. J. Kim (2008)
Learn. Mem. 15, 97-105
   Abstract »    Full Text »    PDF »
Catecholamine and Second Messenger Influences on Prefrontal Cortical Networks of "Representational Knowledge": A Rational Bridge between Genetics and the Symptoms of Mental Illness.
A. F. T. Arnsten (2007)
Cereb Cortex 17, i6-i15
   Abstract »    Full Text »    PDF »
Molecular activity underlying working memory.
P. K. Dash, A. N. Moore, N. Kobori, and J. D. Runyan (2007)
Learn. Mem. 14, 554-563
   Abstract »    Full Text »    PDF »
Isoform specificity of protein kinase Cs in synaptic plasticity.
W. S. Sossin (2007)
Learn. Mem. 14, 236-246
   Abstract »    Full Text »    PDF »
Dopamine D1/5 Receptor-Mediated Long-Term Potentiation of Intrinsic Excitability in Rat Prefrontal Cortical Neurons: Ca2+-Dependent Intracellular Signaling.
L. Chen, J. D. Bohanick, M. Nishihara, J. K. Seamans, and C. R. Yang (2007)
J Neurophysiol 97, 2448-2464
   Abstract »    Full Text »    PDF »
The Common Insecticides Cyfluthrin and Chlorpyrifos Alter the Expression of a Subset of Genes with Diverse Functions in Primary Human Astrocytes.
S. M. Mense, A. Sengupta, C. Lan, M. Zhou, G. Bentsman, D. J. Volsky, R. M. Whyatt, F. P. Perera, and L. Zhang (2006)
Toxicol. Sci. 93, 125-135
   Abstract »    Full Text »    PDF »
Impact of Chronic Psychosocial Stress on Autonomic Cardiovascular Regulation in Otherwise Healthy Subjects.
D. Lucini, G. Di Fede, G. Parati, and M. Pagani (2005)
Hypertension 46, 1201-1206
   Abstract »    Full Text »    PDF »
The Anti-Apoptotic, Glucocorticoid Receptor Cochaperone Protein BAG-1 Is a Long-Term Target for the Actions of Mood Stabilizers.
R. Zhou, N. A. Gray, P. Yuan, X. Li, J. Chen, G. Chen, P. Damschroder-Williams, J. Du, L. Zhang, and H. K. Manji (2005)
J. Neurosci. 25, 4493-4502
   Abstract »    Full Text »    PDF »
A role for prefrontal calcium-sensitive protein phosphatase and kinase activities in working memory.
J. D. Runyan, A. N. Moore, and P. K. Dash (2005)
Learn. Mem. 12, 103-110
   Abstract »    Full Text »    PDF »
Highlights from the literature.
(2005)
Physiology 20, 3-9
   Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882