Alzheimer Disease Centers Directors Meeting Symposia: Original ArticleLater Developments: Molecular Keys to Age-Related Memory ImpairmentBarad, Mark MD, PhD Author Information From the Department of Psychiatry and Biobehavioral Sciences, Brain Research Institute, and Neuropsychiatric Institute, UCLA, Los Angeles, California. Received for publication December 20, 2002; accepted June 16, 2003. This work was supported by grants from NIMH (MH64532), NARSAD and the Tennenbaum Family Initiative. Reprints: Dr. Mark Barad, 3506 Gonda Building, 685 Charles Young Drive South, Los Angeles, CA (e-mail: [email protected]). Alzheimer Disease & Associated Disorders: July 2003 - Volume 17 - Issue 3 - p 168-176 Buy Abstract Age-related memory impairment, a cognitive decline not clearly related to any gross pathology, is progressive and widespread in the population, although not universal. While the mechanisms of learning and memory remain incompletely understood, the study of their molecular mechanisms is already yielding promising approaches toward therapy for such “normal” declines in the efficiency of learning. This review presents the rationale and results for two such approaches. One approach, partial inhibition of the type IV cAMP specific phosphodiesterase, appears to act indirectly. Although little evidence supports an age-related decline in this system, considerable evidence indicates that this approach can facilitate the transition from short-term to long-term memory and thus counterbalance defects in long-term memory, which may be due to other causes. A second approach, inhibition of l-type voltage gated calcium channels (LVGCCs) may be a specific corrective for a molecular pathology of aging, as substantial evidence indicates that an ongoing increase occurs throughout the lifespan in the density of these channels in hippocampal pyramidal cells, with a concomitant reduction in cellular excitability. Because LVGCCs are also crucial to extinction, a paradigm of inhibitory learning, age-related memory impairment may be an unfortunate side effect of a developmental process necessary to the maturation of the ability to suppress inappropriate behavior, an interpretation consistent with the antagonistic pleiotropy theory of aging. © 2003 Lippincott Williams & Wilkins, Inc.