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The Journal of Neuroscience, June 22, 2005, 25(25):5956-5966; doi:10.1523/JNEUROSCI.0880-05.2005

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Development/Plasticity/Repair
Long-Term Potentiation Is Impaired in Middle-Aged Rats: Regional Specificity and Reversal by Adenosine Receptor Antagonists

Christopher S. Rex,¹ Enikö A. Kramár,² Laura L. Colgin,² Bin Lin,² Christine M. Gall,^1,3 and Gary Lynch²

¹Department of Neurobiology and Behavior, University of California, Irvine, California 92697-4550, ²Department of Psychiatry and Human Behavior, University of California, Irvine, California 92612-1695, and ³Department of Anatomy and Neurobiology, University of California, Irvine, California 92697-1275

Memory loss in humans begins early in adult life and progresses thereafter. It is not known whether these losses reflect the failure of cellular processes that encode memory or disturbances in events that retrieve it. Here, we report that impairments in hippocampal long-term potentiation (LTP), a form of synaptic plasticity associated with memory, are present by middle age in rats but only in select portions of pyramidal cell dendritic trees. Specifically, LTP induced with theta-burst stimulation in basal dendrites of hippocampal field CA1 decayed rapidly in slices prepared from 7- to 10-month-old rats but not in slices from young adults. There were no evident age-related differences in LTP in the apical dendrites. Both the adenosine A₁ receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine and a positive AMPA receptor modulator (ampakine) offset age-related LTP deficits. Adenosine produced greater depression of synaptic responses in middle-aged versus young adult slices and in basal versus apical dendrites. These results were not associated with variations in A₁ receptor densities and may instead reflect regional and age-related differences in adenosine clearance. Pertinent to this, brief applications of A₁ receptor antagonists immediately after theta stimulation fully restored LTP in middle-aged rats. We hypothesize that the build-up of extracellular adenosine during theta activity persists into the postinduction period in the basal dendrites of middle-aged slices and thereby activates the A₁ receptor-dependent LTP reversal effect. Regardless of the underlying mechanism, the present results provide a candidate explanation for memory losses during normal aging and indicate that, with regard to plasticity, different segments of pyramidal neurons age at different rates.

Key words: LTP; basal dendrites; hippocampus; DPCPX; aging; A1 adenosine receptor; theta-burst stimulation; reversal

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Received Nov 23, 2004; revised April 20, 2005; accepted May 14, 2005.

This article has been cited by other articles:

				E. A. Kramar, L. Y. Chen, N. J. Brandon, C. S. Rex, F. Liu, C. M. Gall, and G. Lynch Cytoskeletal Changes Underlie Estrogen's Acute Effects on Synaptic Transmission and Plasticity J. Neurosci., October 14, 2009; 29(41): 12982 - 12993. [Abstract] [Full Text] [PDF]

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				G. Burnstock Physiology and Pathophysiology of Purinergic Neurotransmission Physiol Rev, April 1, 2007; 87(2): 659 - 797. [Abstract] [Full Text] [PDF]

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				J. Larson, R. E. Jessen, D. Kim, A.-K. S. Fine, and J. du Hoffmann Age-Dependent and Selective Impairment of Long-Term Potentiation in the Anterior Piriform Cortex of Mice Lacking the Fragile X Mental Retardation Protein J. Neurosci., October 12, 2005; 25(41): 9460 - 9469. [Abstract] [Full Text] [PDF]

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