%0 Journal Article %A Anurag Singh %A Owen D. Jones %A Bruce G. Mockett %A Shane M Ohline %A Wickliffe C. Abraham %T Tumor Necrosis Factor-α-Mediated Metaplastic Inhibition of LTP is Constitutively Engaged in an Alzheimer's Disease Model %D 2019 %R 10.1523/JNEUROSCI.1492-19.2019 %J The Journal of Neuroscience %P 1492-19 %X Long-term potentiation (LTP), a fundamental mechanism of learning and memory, is a highly regulated process. One form of regulation is metaplasticity, i.e., the activity-dependent and long-lasting changes in neuronal state that orchestrate the direction, magnitude and persistence of future synaptic plasticity. We have previously described a heterodendritic metaplasticity effect, whereby strong high-frequency priming stimulation in stratum oriens inhibits subsequent LTP in the stratum radiatum of hippocampal area CA1, potentially by engagement of the enmeshed astrocytic network. This effect may occur due to neurons-glia interactions in response to priming stimulation that leads to the release of gliotransmitters. Here we found in male rats that tumor necrosis factor-α (TNFα) and associated signal transduction enzymes, but not interleukin-1β (IL-1β), were responsible for mediating the metaplasticity effect. Replacing priming stimulation with TNFα incubation reproduced these effects. As TNFα levels are elevated in Alzheimer's disease (AD), we examined whether heterodendritic metaplasticity is dysregulated in a transgenic mouse model of the disease, either before or after amyloid plaque formation. We showed that TNFα and IL-1β levels were significantly increased in aged but not young transgenic mice. Although control LTP was impaired in the young transgenic mice, it was not TNFα-dependent. In the older transgenic mice, however, LTP was impaired in a way that occluded further reduction by heterosynaptic metaplasticity, while LTP was entirely rescued by incubation with a TNFα antibody, but not an IL-1β antibody. Thus, TNFα mediates a heterodendritic metaplasticity in healthy rodents that becomes constitutively and selectively engaged in a mouse model of AD.SIGNIFICANCE STATEMENTThe proinflammatory cytokine tumor necrosis factor-α (TNFα) is known to be capable of inhibiting long-term potentiation (LTP) and is upregulated several fold in brain tissue, serum and cerebrospinal fluid of Alzheimer's disease (AD) patients. However, the mechanistic roles played by TNFα in plasticity and AD remains poorly understood. Here we show that TNFα and its downstream signalling molecules p38 MAPK, ERK, and JNK contribute fundamentally to a long-range metaplastic inhibition of LTP in rats. Moreover, the impaired LTP in aged APP/PS1 mice is rescued by incubation with a TNFα antibody. Thus there is an endogenous engagement of the metaplasticity mechanism in this mouse model of AD, supporting the idea that blocking TNFα might be of therapeutic benefit in the disease. %U https://www.jneurosci.org/content/jneuro/early/2019/09/27/JNEUROSCI.1492-19.2019.full.pdf