First Evidence that Meningeal Interferon-γ Affects Neuronal Connectivity and Social Behavior

Meningeal Interferon and Behavior

A recent study published in Nature magazine links the meningeal immunity to the regulation of social behavior, implicating the meningeal interferon (IFN)-γ and its modulatory effects on the activity of brain cortex GABAergic neurons.

Diseases such as autism spectrum disorder, frontotemporal dementia and schizophrenia are characterized by severe social and immune dysfunction. Little is known about the causes of these mental conditions, and particularly, how the dysfunctional immunity may contribute to altered neural circuits and behavioral deficits.

Recent research, however indicates that the immune system can be involved in the autism spectrum disorder (ASD)-related behavioral deficits in a mouse model of autism. Importantly, it appears that meningeal immunity and cytokines are able to modify behaviors such as learning and memory, probably due to cytokine-neuron interactions in specific cognitive areas.

Now, in the Nature study, Anthony Filiano and colleagues, from the Center for Brain Immunology and Glia, University of Virginia, Charlottesville, Virginia, USA showed that SCID mice (deficient in adaptive immunity; lacking both T and B lymphocytes) exhibit an impaired social behavior. SCID mice also exhibited hyper-connectivity between multiple frontal and insular regions, a phenomenon recently described in children with autism spectrum disorder.

Of note, the authors found that lymphocyte repopulation in SCID mice abolished these changes, restoring the social deficit and improving the aberrant hyper-connectivity, associated with the autism-like behavior.

In a similar fashion, IFN-deficient mice showed social impairment reversed by intra-cerebrospinal injection of IFN-γ. As in the case of SCID mice, IFN-γ -deficient mice also displayed aberrant hyper-connectivity in fronto-cortical/insular regions.

Notably, the intra-cerebrospinal injection of IFN-γ induced an increase in the tonic GABAergic inhibitory current of layer I cortical neurons. This, according to the authors, suggests elevated levels of ambient GABA during application of IFN-γ. Thus, the authors link the IFN-γ-induced up-regulation of the GABAergic inhibitory tone to the social deficits observed in their experiments (see cover image/figure).

While the effects of peripheral cytokines and IFN-γ on the central nervous system and sickness behavior are well documented, the present study reveals a novel role for meningeal immunity in regulating neural activity and social behavior.

The authors have demonstrated that the brain cortical neurons directly respond to IFN-γ derived from meningeal T cells to elevate tonic GABAergic inhibition and prevent aberrant hyper-excitability in the prefrontal cortex.

They concluded that an adaptive immune dysfunction, particularly those mediated by IFN-γ, can produce social dysfunction, suggesting a co-evolutionary link between social behavior and the IFN-γ anti-pathogen immune response.

Source: Nature, 2016 July 21. doi:10.1038/nature18626 [Epub ahead of print]
Read more: Nature

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