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. 2010 Jun 2;30(22):7598-603.
doi: 10.1523/JNEUROSCI.5172-09.2010.

Synaptic correlates of increased cognitive vulnerability with aging: peripheral immune challenge and aging interact to disrupt theta-burst late-phase long-term potentiation in hippocampal area CA1

Timothy R Chapman  1 , Ruth M Barrientos, Jared T Ahrendsen, Steven F Maier, Susan L Patterson
Affiliations

Synaptic correlates of increased cognitive vulnerability with aging: peripheral immune challenge and aging interact to disrupt theta-burst late-phase long-term potentiation in hippocampal area CA1

Timothy R Chapman et al. J Neurosci. .

Abstract

Variability in cognitive functioning increases markedly with age, as does cognitive vulnerability to physiological and psychological challenges. Exploring the basis of this vulnerability may provide important insights into the mechanisms underlying aging-associated cognitive decline. As we have previously reported, the cognitive abilities of aging (24-month-old) F344 x BN rats are generally good, but are more vulnerable to the consequences of a peripheral immune challenge (an intraperitoneal injection of live Escherichia coli) than those of their younger (3-month-old) counterparts. Four days after the injection, the aging, but not the young rats show profound memory deficits, specific to the consolidation of hippocampus-dependent memory processes. Here, we have extended these observations, using hippocampal slices to examine for the first time the combined effects of aging and a recent infection on several forms of synaptic plasticity. We have found that the specific deficit in long-lasting memory observed in the aged animals after infection is mirrored by a specific deficit in a form of long-lasting synaptic plasticity. The late-phase long-term potentiation induced in area CA1 using theta-burst stimulation is particularly compromised by the combined effects of aging and infection-a deficit that can be ameliorated by intra-cisterna magna administration of the naturally occurring antiinflammatory cytokine IL-1Ra (interleukin-1 receptor antagonist). These data support the idea that the combination of aging and a negative life event such as an infection might produce selective, early-stage failures of synaptic plasticity in the hippocampus, with corresponding selective deficits in memory.

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Figures

Figure 1.
Figure 1.
Slices from young and aged rats, with and without a history of infection, respond similarly to test stimuli. A, Stimulus–response curves are not altered by age or a history of infection. Plots of fEPSP slopes (in millivolts per millisecond) at various stimulation intensities for hippocampal slices from young and aged rats with and without a recent history of infection (4 d after injection of E. coli or saline) show no significant differences in basal synaptic transmission in area CA1. B, Paired-pulse facilitation is also not significantly altered by age or a history of infection. Percentage facilitation, calculated from the ratio of the second fEPSP slope to the first fEPSP slope, is shown at interpulse intervals ranging from 50 to 250 ms. No significant differences in PPF were observed across the groups at any of the interpulse intervals examined. Error bars indicate SEM.
Figure 2.
Figure 2.
One-train E-LTP is not greatly altered by age or infection. Mean fEPSP slopes are plotted as a percentage of pretetanus baseline values. E-LTP evoked by a relatively weak stimulus protocol (a single, 1 s, 100 Hz stimulus train) at the Schaffer collateral–CA1 synapse in hippocampal slices from aged and young rats, with and without a previous history of infection. Slices were prepared from animals 4 d after injection of E. coli or vehicle. Neither age nor a history of infection had a significant effect on E-LTP in area CA1. The insets show representative traces. Error bars indicate SEM.
Figure 3.
Figure 3.
Age and infection differentially affect distinct types of L-LTP. Experiments examining two forms of L-LTP in aged and young rats, with and without a previous history of infection. Slices were prepared from animals 4 d after the E. coli or vehicle injections. L-LTP was elicited at the Schaffer collateral–CA1 synapse using one of two distinct stimulus protocols: a four-train protocol (four 1 s, 100 Hz stimulus trains, delivered 5 min apart) and a theta-burst protocol (12 bursts of 4 pulses at a 100 Hz, delivered 200 ms apart). A, The L-LTP evoked by the intense, second-long bouts of high-frequency stimulation (the 4-train protocol) was not significantly affected by age or infection. B, In contrast, infection suppressed the full expression of theta-burst L-LTP, and aging greatly exacerbated this effect. The insets show representative traces. Error bars indicate SEM.
Figure 4.
Figure 4.
Blocking the actions of the IL-1β in the CNS ameliorates the effect of peripheral infection on theta-burst L-LTP in aged rats. The antiinflammatory cytokine IL-1Ra or vehicle was injected into the cisternae magna of aged rats, and immediately afterward the rats received an intraperitoneal injection of either E. coli or vehicle. Hippocampal slices were prepared from the animals 4 d after the injections, and Schaffer collateral–CA1 synapses were stimulated using the theta-burst protocol. Infusion of exogenous IL-1Ra into the brain greatly reduced the E. coli-induced impairment in theta-burst L-LTP. The insets show representative traces. Error bars indicate SEM.
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