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 behavior, such as spatial learning and memory1. Here we show that meningeal immunity is also critical for social behavior; 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 behavior and interferon-gamma (IFN-γ) driven responses. Concordantly, we demonstrate that inhibitory neurons respond to IFN-γ and increase GABAergic currents in projection neurons, suggesting that IFN-γ is a molecular link between meningeal immunity and neural circuits recruited for social behavior. Meta-analysis on the transcriptomes of a range of organisms revealed that rodents, fish, and flies elevate IFN-γ/JAK-STAT–dependent gene signatures in a social context, suggesting that the IFN-γ signaling pathway could mediate a co-evolutionary link between social/aggregation behavior 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 behavior and an anti-pathogen immune response driven by IFN-γ signaling.

Understanding the functions and relationships of the glymphatic system and meningeal lymphatics

“…Notably, IL-4 and IL-13 production by meningeal T cells appears to contribute to the maintenance of cognitive function in mice (74,95). Furthermore, production of IFN-γ in the SAS directly regulates social behavior in mice (96).…”

The Role of the Immune System in Autism Spectrum Disorder

“…Further studies should attempt to elucidate the network of interactions leading to systemic immune dysregulation in individuals with autism, in particular the role of IL-17 and the Th1/Th2 balance, with guidance from observations from the MIA model. Given the ability of the immune environment to affect behavior (Filiano et al, 2016), parsing out the different pathways, especially over the rapidly changing immune environment in early childhood as well as the heterogeneity that is inherent in ASD, remains both a challenge and an opportunity for the field. ............................................................................................................................................................. …”

Beyond the Art of BART: Bilateral Affective Reprocessing of Thoughts as a Dynamic Model for Psychotherapy Across the Lifespan

“…Unexpected role of interferon gamma in regulating neuronal connectivity and social behaviour, [28] provides an opportunity for further research into the efficacy of BART psychotherapy Human meningeal immunity was previously known to influence spatial learning and memory and has now been shown to affect social behaviour. Mice, whose adaptive immunity was compromised, showed enhanced connectivity of the frontal cortex and this was associated with marked deficits in their social behaviour.…”