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The Journal of Neuroscience, December 15, 2001, 21(24):9744-9756

Elevated Postsynaptic [Ca²⁺]_i and L-Type Calcium Channel Activity in Aged Hippocampal Neurons: Relationship to Impaired Synaptic Plasticity

Olivier Thibault, Robert Hadley, and Philip W. Landfield

Department of Molecular and Biomedical Pharmacology, MS-307 University of Kentucky College of Medicine, Lexington, Kentucky 40536-0298

Considerable evidence supports a Ca²⁺ dysregulation hypothesis of brain aging and Alzheimer's disease. However, it is still not known whether (1) intracellular [Ca²⁺]_i is altered in aged brain neurons during synaptically activated neuronal activity; (2) altered [Ca²⁺]_i is directly correlated with impaired neuronal plasticity; or (3) the previously observed age-related increase in L-type voltage-sensitive Ca²⁺ channel (L-VSCC) density in hippocampal neurons is sufficient to impair synaptic plasticity. Here, we used confocal microscopy to image [Ca²⁺]_i in single CA1 neurons in hippocampal slices of young-adult and aged rats during repetitive synaptic activation. Simultaneously, we recorded intracellular EPSP frequency facilitation (FF), a form of short-term synaptic plasticity that is impaired with aging and inversely correlated with cognitive function. Resting [Ca²⁺]_i did not differ clearly with age. Greater elevation of somatic [Ca²⁺]_i and greater depression of FF developed in aged neurons during 20 sec trains of 7 Hz synaptic activation, but only if the activation triggered repetitive action potentials for several seconds. Elevated [Ca²⁺]_i and FF also were negatively correlated in individual aged neurons. In addition, the selective L-VSCC agonist Bay K8644 increased the afterhyperpolarization and mimicked the depressive effects of aging on FF in young-adult neurons. Thus, during physiologically relevant firing patterns in aging neurons, postsynaptic Ca²⁺ elevation is closely associated with altered neuronal plasticity. Moreover, selectively increasing postsynaptic L-VSCC activity, as occurs in aging, negatively regulated a form of short-term plasticity that enhances synaptic throughput. Together, the results elucidate novel processes that may contribute to impaired cognitive function in aging.

Key words: frequency facilitation; imaging; homeostasis; dendrites; repetitive activation; memory

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21249744-13$05.00/0

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