Michael Douglas Reed # 1 2, Yeong Shin Yim # 1 2, Ralf D Wimmer 1 2 3, Hyunju Kim 4, Changhyeon Ryu 1 2, Gwyneth Margaret Welch 1 2, Matias Andina 1 2, Hunter Oren King 2, Ari Waisman 5, Michael M Halassa 1 2 3, Jun R Huh 6 7, Gloria B Choi 8 9
a, Body temperature profile after injection of saline (vehicle) or LPS in offspring of mothers injected with PBS (PBS offspring) (vehicle, n = 11 and LPS, n = 11 mice, from 5 independent experiments). The initial spike in body temperature is due to handling stress. b, c, Mice were tested for sociability (percentage of time spent investigating social object/total time spent investigating both social and inanimate objects) one day before LPS injection (pre-test; pre). Mice were then tested for sociability four hours after injection with vehicle or LPS (test). PBS offspring + vehicle, n = 10; PBS offspring + LPS, n = 9; MIA offspring + vehicle, n = 10; MIA offspring + LPS, n = 12; wild type (WT) + vehicle, n = 8; wild type + LPS, n = 11; Cntnap2 mutant + vehicle, n = 11; Cntnap2 mutant + LPS, n = 11; Fmr1 mutant + vehicle, n = 11; Fmr1 mutant + LPS, n = 15; Shank3 mutant + vehicle, n = 8; Shank3 mutant + LPS, n = 10; from 3 independent experiments. I.p., intraperitoneal. d, Virus encoding the inhibitory DREADD (AAV2-hSyn-DIO-hM4D(Gi)-mCherry) was targeted to the ventral part of the lateral preoptic nucleus (vLPO) of Vgat–Cre MIA mice. Scale bar, 2 mm. e, Body temperature profile after injection with vehicle or CNO. f, g, Mice were tested for sociability one day before injection (pre). On the following two days, mice received counterbalanced injections of either vehicle or CNO. Sociability was assessed two hours after injection. For experiments in d–g, n = 9 for all groups, from 2 independent experiments. All n values refer to the number of mice used. *P < 0.05, **P < 0.01, calculated by two-way repeated-measures analysis of variance (ANOVA) with Bonferroni’s (a, e) or Sidak’s (c) post-hoc tests, or one-way repeated-measures ANOVA with Tukey’s post-hoc test (g). Graphs are mean ± s.e.m.a, Mice were tested for sociability one day before injection (pre). The following day, blocking antibody against IL-17a (anti-IL-17a) or isotype-control antibody (isotype) was administered intracerebroventricularly (i.c.v.), 30 min before injection of vehicle or LPS. Sociability was assessed four hours after injection of vehicle or LPS (test). PBS offspring + vehicle + isotype, n = 9; PBS offspring + LPS + isotype, n = 11; MIA offspring + vehicle + isotype, n = 10; MIA offspring + LPS + isotype, n = 10; MIA offspring + LPS + anti-IL-17a, n = 10; from 7 independent experiments. b–d, Firing rate of neurons of the S1DZ before and four hours after injection of vehicle or LPS, in PBS and MIA offspring pre-treated with isotype-control antibody or blocking antibody against IL-17a. c, Example raster plot with firing rate profile before (baseline) and after (test) treatment with LPS, from an PBS mouse and MIA mouse pre-treated with isotype-control antibody. d, Normalized firing-rate (FR) change after treatment represented as box-and-whisker plots, indicating median, interquartile range and data limits as defined by Tukey. PBS offspring + vehicle + isotype, n = 65 cells; PBS offspring + LPS + isotype, n = 42 cells; PBS offspring + LPS + anti-IL-17a, n = 40 cells; MIA offspring + vehicle + isotype, n = 75 cells; MIA offspring + LPS + isotype, n = 48 cells; MIA offspring + LPS + anti-IL-17a, n = 43 cells; from 2 PBS offspring and 2 MIA offspring in 12 independent experiments. e, Lentivirus encoding either EYFP or enhanced green fluorescent protein (EGFP) fused to nuclear Cre (nCre) was bilaterally injected into the S1DZ of IL-17Rafl/fl MIA offspring. Scale bar, 200 μm. f, g, Mice were tested for sociability one day before injection (pre). The following day, mice were tested for sociability four hours after LPS injection (test). For experiments in e, f, Il-17rafl/fl;EYFP, n = 9 and Il-17rafl/fl;EGFP:nCre, n = 10; from 5 independent experiments. Unless otherwise indicated, n values refer to the number of mice used. Statistics calculated by two-way repeated-measures ANOVA with Bonferroni’s post-hoc test (a, f) or two-way ANOVA with Tukey’s post-hoc test (d). Graphs are mean ± s.e.m.
Comment in Interleukin-17: A Social Cytokine. Hoogenraad CC, Riol-Blanco L. Cell. 2020 Apr 30;181(3):517-519. doi: 10.1016/j.cell.2020.03.060. PMID: 32359435
Figure 1. IL-17 Promotes Sociability in Mice with Neurodevelopmental Disorders (A) In comparison with control mice, maternal immune inflammation (MIA) offspring display increased neural activity of the dysgranular zone of the primary somatosensory cortex of the brain (S1DZ), which is manifested as (1) an increase in the number of FOS+ neurons and (2) higher firing rates of neurons of the S1DZ. This neural hyperactivity induces a sociability deficit in mice. (B) LPS injection increases IL-17 levels systemically, which reaches the brain and binds its receptor, IL17RA, on the surface of S1DZ cortical neurons, bringing neural activity down to normal levels, which translates into a temporal rescue in sociability.aec35f8fc65bef6b7d36c25b8dd43c61
