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TNFα and IL-1β but not IL-18 Suppresses Hippocampal Long-Term Potentiation Directly at the Synapse

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Abstract

CNS inflammatory responses are linked to cognitive impairment in humans. Research in animal models supports this connection by showing that inflammatory cytokines suppress long-term potentiation (LTP), the best-known cellular correlate of memory. Cytokine-induced modulation of LTP has been previously studied in vivo or in brain slices, two experimental approaches containing multiple cell populations responsive to cytokines. In their target cells, cytokines commonly increase the expression of multiple cytokines, thus increasing the complexity of brain cytokine networks even after single-cytokine challenges. Whether cytokines suppress LTP by direct effects on neurons or by indirect mechanisms is still an open question. Here, we evaluated the effect of a major set of inflammatory cytokines including tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β) and interleukin-18 (IL-18) on chemically-induced LTP (cLTP) in isolated hippocampal synaptosomes of mice, using fluorescence analysis of single-synapse long-term potentiation (FASS-LTP). We found that TNFα and IL-1β suppress synaptosomal cLTP. In contrast, cLTP was not affected by IL-18, at a concentration previously shown to block LTP in hippocampal slices. We also found that IL-18 does not impair cLTP or brain-derived neurotrophic factor (BDNF) signaling in primary hippocampal neuronal cultures. Thus, using both synaptosomes and neuron cultures, our data suggest that IL-18 impairs LTP by indirect mechanisms, which may depend on non-neuronal cells, such as glia. Notably, our results demonstrate that TNFα and IL-1β directly suppress hippocampal plasticity via neuron-specific mechanisms. A better understanding of the brain’s cytokine networks and their final molecular effectors is crucial to identify specific targets for intervention.

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Acknowledgements

Work in the authors’ lab is supported by National Institutes of Health Grants R21-AG048506, P01-AG000538 and RO1-AG34667 (to C. W. C.), as well as by UC MEXUS-CONACYT Grant CN-16-170 (to G. A. P. and C. W. C.).

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  1. Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, 92697, USA

    G. Aleph Prieto, Liqi Tong, Erica D. Smith & Carl W. Cotman

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  1. G. Aleph Prieto
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  2. Liqi Tong
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Correspondence to G. Aleph Prieto.

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We are pleased to contribute to this issue dedicated to Eli Michaelis. Over his career, he has generated a legacy of key discoveries to the field of glutamate as a neurotransmitter in the brain from its metabolism, glia neuron interactions, to its role in brain excitability. Our work and that of others builds on his contributions. He has been and will continue to be a great friend, scholar and colleague.

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Prieto, G.A., Tong, L., Smith, E.D. et al. TNFα and IL-1β but not IL-18 Suppresses Hippocampal Long-Term Potentiation Directly at the Synapse. Neurochem Res 44, 49–60 (2019). https://doi.org/10.1007/s11064-018-2517-8

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  • DOI: https://doi.org/10.1007/s11064-018-2517-8

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