title: Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour.
abstract: Immune dysfunction is commonly associated with several neurological and mental disorders. Although the mechanisms by which peripheral immunity may influence neuronal function are largely unknown, recent findings implicate meningeal immunity influencing behaviour, such as spatial learning and memory. Here we show that meningeal immunity is also critical for social behaviour; mice deficient in adaptive immunity exhibit social deficits and hyper-connectivity of fronto-cortical brain regions. Associations between rodent transcriptomes from brain and cellular transcriptomes in response to T-cell-derived cytokines suggest a strong interaction between social behaviour and interferon-γ (IFN-γ)-driven responses. Concordantly, we demonstrate that inhibitory neurons respond to IFN-γ and increase GABAergic (γ-aminobutyric-acid) currents in projection neurons, suggesting that IFN-γ is a molecular link between meningeal immunity and neural circuits recruited for social behaviour. Meta-analysis of the transcriptomes of a range of organisms reveals that rodents, fish, and flies elevate IFN-γ/JAK-STAT-dependent gene signatures in a social context, suggesting that the IFN-γ signalling pathway could mediate a co-evolutionary link between social/aggregation behaviour and an efficient anti-pathogen response. This study implicates adaptive immune dysfunction, in particular IFN-γ, in disorders characterized by social dysfunction and suggests a co-evolutionary link between social behaviour and an anti-pathogen immune response driven by IFN-γ signalling.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Filiano
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Tustison
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Marsh
authors.forename: Wendy
authors.initials: W
authors.lastname: Baker
authors.forename: Igor
authors.initials: I
authors.lastname: Smirnov
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Overall
authors.forename: Sachin P
authors.initials: SP
authors.lastname: Gadani
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Turner
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Weng
authors.forename: Sayeda Najamussahar
authors.initials: SN
authors.lastname: Peerzade
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Lee
authors.forename: Michael M
authors.initials: MM
authors.lastname: Scott
authors.forename: Mark P
authors.initials: MP
authors.lastname: Beenhakker
authors.forename: Vladimir
authors.initials: V
authors.lastname: Litvak
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kipnis
mesh_terms: D000818:Animals; D004331:Drosophila melanogaster / Q000235:genetics; D005260:Female; D059330:GABAergic Neurons / Q000378:metabolism; D007371:Interferon-gamma / Q000502:physiology*; D008297:Male; D008578:Meninges / Q000166:cytology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009434:Neural Pathways; D017397:Prefrontal Cortex / Q000166:cytology / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D012919:Social Behavior; D013601:T-Lymphocytes / Q000276:immunology; D059467:Transcriptome; D015027:Zebrafish / Q000235:genetics
chemical_list: D007371:Interferon-gamma