Forgetting About Protein Kinase A

Science's STKE  18 Nov 2003:
Vol. 2003, Issue 209, pp. tw444-TW444
DOI: 10.1126/stke.2092003TW444

All too often, aging is accompanied by memory deficits. Various studies have implicated activation of protein kinase A (PKA) signaling in long-term potentiation (a use-dependent increase in synaptic efficacy) and consolidation of long-term memory in the hippocampus. Consequently, activation of PKA is an attractive therapeutic target for interventions aimed at alleviating aging-related memory deficits. However, different brain regions mediate different forms of memory, and in some of these regions the neurobiological correlates of memory dysfunction are less well understood (see Baxter). Ramos et al. infused an activator or an inhibitor of PKA into the prefrontal cortex of rats and tested their spatial working memory (which is associated with the prefrontal cortex). In aged rats with impaired memory function, memory was improved by inhibiting PKA and impaired by activating PKA. The greater the aging-related cognitive deficit, the greater the effects of modulating PKA. Similarly, inhibiting phosphodiesterase impaired spatial working memory in aged monkeys. The authors used Western, immunohistochemical, and gel-shift analyses to compare activity of PKA signaling pathways in the cerebral cortex, hippocampus, and cerebellum of young and aged rats. They observed increased numbers of cells staining for phosphorylated CREB (cAMP response element-binding protein), more intense phospho-CREB staining per cell, and enhanced binding to the cAMP response element in the prefrontal cortex--but not the hippocampus or cerebellum--of aged rats. Thus, in contrast to the hippocampus, activation of PKA pathways appears to be associated with aging-related memory deficits in the prefrontal cortex.

B. P. Ramos, S. G. Birnbaum, I. Lindenmayer, S. S. Newton, R. S. Duman, A. F. T. Arnsten, Dysregulation of protein kinase A signaling in the aged prefrontal cortex: New strategy for treating age-related cognitive decline. Neuron 40, 835-845 (2003). [Online Journal]

M. G. Baxter, Age-related memory impairment: Is the cure worse than the disease? Neuron 40, 669-670 (2003). [Online Journal]