RECEPTOR SUBTYPE-DEPENDENT ROLE OF INTERLEUKIN-4 IN EXCITATORY AND INHIBITORY NEURONAL NETWORKS

The pleiotropic type 2 cytokine interleukin-4 (IL-4) has a direct impact on neurons. We recently showed that IL-4 not only has neuroprotective and –regenerative effects, but also plays a role in neuronal homeostasis by regulating synaptic transmission. Neuronal IL-4 receptor alpha (IL-4Rα)-deficient mice showed decreased frequencies of both excitatory and inhibitory miniature postsynaptic currents, but surprisingly neuronal network activity in cortex was increased in vivo (Hanuscheck et al., 2022). IL-4 signals either through the IL-4R type I, consisting of the co‑chains IL-4Rα and IL-2Rγ, or through IL-4R type II, comprising IL-4Rα and IL-13Rα1. We confirmed differential expression of both subtypes in brain and spinal cord. To distinguish whether the effects of IL-4 are receptor subtype-specific and mediated via inhibitory or excitatory activity, we use mice deficient for the different chains in excitatory (CamKII cre) and inhibitory (Gad 2 cre) neurons. Microelectrode array (MEA) recordings of acute mouse brain slices showed that IL-4 induces an increase of spontaneous activity and evoked activity changes in the motor cortex of WT mice. In slices from il4ra^fl/fl.CamkII cre mice IL-4 effects are abolished, whereas il4ra^fl/fl.Gad2 Cre neuronal networks are still responsive to IL-4. Therefore, we conclude that the IL‑4‑induced increase of neuronal network activity is likely mediated by excitatory neurons.
Hanuscheck et al., N. (2022). Interleukin-4 receptor signaling modulates neuronal network activity. Journal of Experimental Medicine, S. 219(6):e20211887.