IL-4 shapes microglia-dependent pruning of the cerebellum during postnatal development

• Published in: Neuron (Cambridge, Mass.) Vol. 111; no. 21; pp. 3435 - 3449.e8
• Main Authors: Guedes, Joana R, Ferreira, Pedro A, Costa, Jéssica, Laranjo, Mariana, Pinto, Maria J, Reis, Tiago, Cardoso, Ana Maria, Lebre, Carolina, Casquinha, Maria, Gomes, Marcos, Shkatova, Viktoriya, Pereira, Marta, Beltrão, Nuno, Hanuscheck, Nicholas, Greenhalgh, Andrew D, Vogelaar, Christina Francisca, Carvalho, Ana Luísa, Zipp, Frauke, Cardoso, Ana Luísa, Peça, João
• Format: Journal Article
• Language: English
• Published: United States 01.11.2023
• Subjects: Animals; Brain; Cerebellum; Cytokines; Humans; Interleukin-4; Microglia; allergies; ADHD; pruning; development; hyperactivity; granule cells; type 2 cytokines; IL-4; microglia; cerebellum
• ISSN: 1097-4199
• DOI: 10.1016/j.neuron.2023.09.031

Interleukin-4 (IL-4) is a type 2 cytokine with pleiotropic functions in adaptive immunity, allergies, and cognitive processes. Here, we show that low levels of IL-4 in the early postnatal stage delineate a critical period in which microglia extensively prune cerebellar neurons. Elevating the levels of this cytokine via peripheral injection, or using a mouse model of allergic asthma, leads to defective pruning, permanent increase in cerebellar granule cells, and circuit alterations. These animals also show a hyperkinetic and impulsive-like phenotype, reminiscent of attention-deficit hyperactivity disorder (ADHD). These alterations are blocked in Il4rα ::Cx3cr1-CreER mice, which are deficient in IL-4 receptor signaling in microglia. These findings demonstrate a previously unknown role for IL-4 during a neuroimmune critical period of cerebellar maturation and provide a first putative mechanism for the comorbidity between allergic disease and ADHD observed in humans.