| First Author | Singh A | Year | 2019 |
| Journal | J Neurosci | Volume | 39 |
| Issue | 46 | Pages | 9083-9097 |
| PubMed ID | 31570539 | Mgi Jnum | J:281459 |
| Mgi Id | MGI:6377929 | Doi | 10.1523/JNEUROSCI.1492-19.2019 |
| Citation | Singh A, et al. (2019) Tumor Necrosis Factor-alpha-Mediated Metaplastic Inhibition of LTP Is Constitutively Engaged in an Alzheimer's Disease Model. J Neurosci 39(46):9083-9097 |
| abstractText | 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 neuron-glia interactions in response to priming stimulation that leads to the release of gliotransmitters. Here we found in male rats that TNFalpha and associated signal transduction enzymes, but not interleukin-1beta (IL-1beta), were responsible for mediating the metaplasticity effect. Replacing priming stimulation with TNFalpha incubation reproduced these effects. As TNFalpha levels are elevated in Alzheimer's disease, 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 TNFalpha and IL-1beta levels were significantly increased in aged but not young transgenic mice. Although control LTP was impaired in the young transgenic mice, it was not TNFalpha-dependent. In the older transgenic mice, however, LTP was impaired in a way that occluded further reduction by heterosynaptic metaplasticity, whereas LTP was entirely rescued by incubation with a TNFalpha antibody, but not an IL-1beta antibody. Thus, TNFalpha mediates a heterodendritic metaplasticity in healthy rodents that becomes constitutively and selectively engaged in a mouse model of Alzheimer's disease.SIGNIFICANCE STATEMENT The proinflammatory cytokine TNFalpha is known to be capable of inhibiting LTP and is upregulated several-fold in brain tissue, serum, and CSF of Alzheimer's disease (AD) patients. However, the mechanistic roles played by TNFalpha in plasticity and AD remain poorly understood. Here we show that TNFalpha and its downstream signaling 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 TNFalpha antibody. Thus, there is an endogenous engagement of the metaplasticity mechanism in this mouse model of AD, supporting the idea that blocking TNFalpha might be of therapeutic benefit in the disease. |
