Neuroscience

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Synapses are important sites for the transmission of information between neurons, belong to key components of neuronal networks, and possess functions that control neural circuits. Cytokines such as IFN-γ, TNF-a, IL-1, IL-4, and IL-6 are now identified as key regulators of social behavior as well as learning and memory. Different cytokines shape synaptic function at multiple levels, ranging from fine regulation of neurotransmission to modulation of synapse number to influencing global neuronal networks and complex behavior. In addition, some immune cytokines can even regulate the central nervous system (CNS) and play an important role in brain circuit development. Further research into the mechanisms of cytokine effects on synapses is now driving new cytokine therapies for the treatment of potential synaptic dysfunction.

Immune cytokine impact on network activity in pathologyFigure 1. Immune cytokine impact on network activity in pathology. (Zipp F, et al., 2023)

Synapse & Cytokines

Experiments have shown that cytokines can directly influence the function and structure of both basic excitatory and inhibitory synapses. IL-1β is part of the IL-1 family of cytokines, and in vitro studies have demonstrated that IL-1β can act at excitatory synapses and increase neuronal excitability. In contrast, IL-6 normally acts as an inhibitor of basal neural activity.

IL-4 acts as a key regulator of inhibitory effects on synaptic function. It has been found that IL-4 receptor alpha (IL-4Rα) is expressed presynaptically in excitatory and inhibitory hippocampal neurons, and that deficiency of IL-4Rα in mice leads to a reduction in the pool of neurotransmitter-containing synaptic vesicles in these neurons, which, in turn, reduces basal neuronal activity. Thus, IL-4 and IL-4Rα play inhibitory roles in maintaining CNS synaptic function, neural excitability, and overall behavior.

IFN-γ, derived from meningeal T cells, has also emerged as a potent regulator of inhibitory neurotransmission. IFN-γ is normally produced by T cells and natural killer cells and is a potent amplifier of peripheral inflammation. Learning and memory deficits are present in mice lacking T cells. In addition, meningeal T cell-derived IFN-γ acts on prefrontal cortex-expressing receptors to increase currents in projection neurons.

TNF-α is a major driver of neuronal excitability and regulates excitatory neurons primarily through AMPAR. In addition, while IL-1β normally inhibits voltage-gated ion channels to limit excitability, TNF-α can increase neuronal excitability by enhancing the transcription of related genes in vivo.

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Reference

  1. Zipp F, Bittner S, Schafer D P. (2023). Cytokines as emerging regulators of central nervous system synapses[J]. Immunity. 56(5): 914-925.
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