Protein kinase C activity is associated with prefrontal cortical decline in aging

Brennan, Avis R.; Yuan, Peixiong; Dickstein, Dara L.; Rocher, Anne B.; Hof, Patrick R.; Manji, Husseini; Arnsten, Amy F.T.

doi:10.1016/j.neurobiolaging.2007.08.020

« Previous Next »Neurobiology of Aging
Volume 30, Issue 5 , Pages 782-792, May 2009

Protein kinase C activity is associated with prefrontal cortical decline in aging

Avis R. Brennan
- Yale University School of Medicine, Department of Neurobiology, 333 Cedar Street, New Haven, CT 06511, USA
Peixiong Yuan
- National Institute of Mental Health (NIMH), Laboratory of Molecular Pathophysiology, 35 Convent Drive, MSC 3711, Bethesda, MD 20892, USA
Dara L. Dickstein
- Mount Sinai School of Medicine, Department of Neuroscience, One Gustave L. Levy Place, New York, NY 10029, USA
Anne B. Rocher
- Mount Sinai School of Medicine, Department of Neuroscience, One Gustave L. Levy Place, New York, NY 10029, USA
- Current address: Boston University School of Medicine, Department of Anatomy and Neurobiology, 715 Albany Street, L, Boston, MA 02118, USA.
Patrick R. Hof
- Mount Sinai School of Medicine, Department of Neuroscience, One Gustave L. Levy Place, New York, NY 10029, USA
Husseini Manji
- National Institute of Mental Health (NIMH), Laboratory of Molecular Pathophysiology, 35 Convent Drive, MSC 3711, Bethesda, MD 20892, USA
Amy F.T. Arnsten
- Yale University School of Medicine, Department of Neurobiology, 333 Cedar Street, New Haven, CT 06511, USA
- Corresponding author at: Yale University School of Medicine, Department of Neurobiology, 333 Cedar Street, SHM C300, New Haven, CT 06511, USA. Tel.: +1 203 785 4431; fax: +1 203 785 5263.

Received 23 May 2007; received in revised form 16 July 2007; accepted 22 August 2007. published online 05 October 2007.

Abstract

Aging is associated with deficiencies in the prefrontal cortex, including working memory impairment and compromised integrity of neuronal dendrites. Although protein kinase C (PKC) is implicated in structural plasticity, and overactivation of PKC results in working memory impairments in young animals, the role of PKC in prefrontal cortical impairments in the aged has not been examined. This study provides the first evidence that PKC activity is associated with prefrontal cortical dysfunction in aging. Pharmacological inhibition of PKC with chelerythrine rescued working memory impairments in aged rats and enhanced working memory in aged rhesus monkeys. Improvement correlated with age, with older monkeys demonstrating a greater degree of improvement following PKC inhibition. Furthermore, PKC activity within the prefrontal cortex was inversely correlated with the length of basal dendrites of prefrontal cortical neurons, as well as with working memory performance in aged rats. Together these findings indicate that PKC is dysregulated in aged animals and that PKC inhibitors may be useful in the treatment of cognitive deficits in the elderly.

Keywords: Prefrontal cortex, Aging, Working memory, Protein kinase C, Dendritic spines, Chelerythrine, Dendrites