Aging and an Immune Challenge Interact to Produce Prolonged, but Not Permanent Reductions in Hippocampal L-LTP and mBDNF in a Rodent Model with Features of Delirium

Abstract

Aging increases the risk of abrupt declines in cognitive function after an event that triggers immune system activation (e.g. surgery, infection, or injury). This phenomenon is poorly understood, but rodent models may provide clues. We have previously shown that aging (24-month-old) F344xBN rats generally don’t show significant physical or cognitive impairments. However, their brains mount an exaggerated inflammatory response to signals triggered by a peripheral immune challenge (an intraperitoneal injection of E. coli or laparotomy). Their hippocampal levels of the pro-inflammatory cytokine IL-1β are significantly elevated for at least 8, but generally less than 14 days after infection or surgery. This IL-1β elevation is mirrored by prolonged deficits in a hippocampus-dependent long-term memory task. In contrast, young (3-month-old) counterparts exhibit only transient elevations in IL-1β that drop to near baseline levels within 24 hours. We previously demonstrated that theta burst-evoked late-phase long-term potentiation (L-LTP) – a BDNF-dependent form of synaptic plasticity – is impaired in hippocampal area CA1 of aged animals 4 days after infection. Also, levels of mature brain-derived neurotrophic factor (mBDNF) – the protein isoform required for stabilization of L-LTP – are reduced in hippocampal synaptoneurosomes of aged animals at the same time point. In this study, we investigated whether the deficits in L-LTP and mBDNF persist in parallel with the elevation in IL-1β and impairment in memory. This was the case, consistent with the idea that an exaggerated brain inflammatory response may compromise memory consolidation in part by altering availability of mBDNF to stabilize memory-related synaptic plasticity.

Significance Statement Not all cognitive decline is gradual. Older individuals – even those previously healthy and high functioning – are more likely to experience an abrupt decline in mental function (termed delirium) after immune challenge. Even if this is temporary, it is associated with increased risk of ultimately developing dementia. Although clinically important, this phenomenon is much less studied than gradual senescence and aging-associated neurodegenerative disorders. Here we use a naturalistic rodent model to further test the hypothesis that the combination of age and an immune challenge may trigger an exaggerated inflammatory state in the brain, which in turn, disrupts molecular systems critical for memory. These studies may provide mechanistic insights into the earliest stages of inflammation-driven failures of memory-related synaptic plasticity.