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

Abstract

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 A 1 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 A 1 receptor densities and may instead reflect regional and age-related differences in adenosine clearance. Pertinent to this, brief applications of A 1 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 A 1 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.

Synaptic plasticity in early aging

“…In our studies demonstrating LTP impairments in middle-age, the theta burst responses used to induce LTP were not detectably different in slices from young adult and middle-aged rats, but the degree to which they facilitated within a theta train was greatly depressed in the latter group (Rex et al, 2005). Burst facilitation was fully restored by infusion of an adenosine A1 receptor antagonist.…”

“…Increasing the size of the theta burst responses, either by enhancing release or positively modulating post-synaptic glutamate receptors, restored LTP in the basal dendrites of middleaged slices to young adult levels (Rex et al, 2005). This tells us that the mechanisms for consolidation (along with those for induction and expression of LTP) are intact in middleaged slices, but that a partial failure has occurred in the pathways leading to them.…”

“…As predicted if there were impairments to clearance, response recovery was slower in middle-aged than young adult slices and in the basal versus apical dendritic fields. There were no evident age-related or regional differences in the concentrations of A1 receptors (Rex et al, 2005) and the affinity of rat brain A1 receptors is reported not to change with age (Cunha et al, 1995;Sperlagh et al, 1997). Extracellular adenosine levels are elevated in brains (Murillo-Rodriguez et al, 2004) and hippocampal slices (Sperlagh et al, 1997) from aged (22-24 months) rats with a trend in the same direction in slices from 12-month-old rats.…”

“…With this protocol, the drug was not available to modify LTP induction and initial expression events but was present throughout the consolidation phase. The treatment proved sufficient to restore LTP almost to levels found in young adults (Rex et al, 2005). It appears then that the LTP problem in the basal dendrites arises from (i) an increase in adenosine release, (ii) a failure of adenosine clearance, or (iii) enhanced signaling through A1 receptors.…”

“…We recently carried out an explicit test for deficits in the conventional CA1/hippocampal slice preparation and found that the degree of stable potentiation produced by a train of theta burst stimulation (TBS) was no different in CA1 stratum (str.) radiatum of slices prepared from young adult (1-2 months) versus middleaged (8-10 months) rats (Rex et al, 2005). Such results could simply indicate that LTP does not deteriorate by middle age and therefore memory impairments occurring in midadulthood are attributable to factors other than a loss of synaptic plasticity.…”