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

Meningeal Interferon Social Behavior
Meningeal Interferon – Social 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.

Social dysfunction manifests in several neurological and mental disorders. 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.

An imbalance of cytokines, a disparity of T cell subsets, and overall immune dysfunction is often associated with abovementioned disorders. However, the fundamental mechanism(s) by which dysfunctional immunity may interfere with neural circuits and contribute to behavioral deficits remain unclear.

Recent research 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).

As discussed by the authors, it is intriguing that IFN-γ, predominately thought of as an anti-pathogen cytokine, can play such a profound role in maintaining proper social function. They hypothesized that there was co-evolutionary pressure to increase an anti-pathogen response as sociability increased, and that the IFN-γ pathway may have influenced this co-evolution.

To test this hypothesis, they analyzed metadata of publically available transcriptomes from multiple organisms including the rat, mouse, zebrafish, and fruit flies. Using GSEA, they determined transcripts from social rodents (acutely group-housed) are enriched for an IFN-γ responsive gene signature. Conversely, rodents that experienced social isolation demonstrated a dramatic loss of the IFN-γ responsive gene signature.

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.

These data suggest that social deficits in numerous neurological and psychiatric disorders may result from impaired circuitry homeostasis derived from dysfunctional immunity.

Importantly, it is also plausible that subtle homeostatic changes in meningeal immunity may also contribute to modulating neuronal circuits that are responsible for our everyday behaviors and personality. Given this communication between immunity and neuronal circuits, it is intriguing to hypothesize that these pathways may be vulnerable to manipulation by fast-evolving pathogens.

The authors 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

Related stories you may like:
Interferon and the Central Nervous System
Interferon-γ Levels and Chronic Fatigue Syndrome
Hyperactive Interferon System Choroid Plexus Linked To Aging and Cognitive Dysfunction
Anxiety Linked to High IFN-γ and TNF-α