No mouse is an island
Group living offers many benefits, including companionship and shared resources for food and safety, but it also comes with drawbacks, such as social conflict and an increased likelihood for infectious disease transmission. Interestingly, both dysfunctional social behaviors and immune system dysregulation are clinical symptoms associated with several neurologic and mental disorders. These observations have suggested linkages between immune responses and social behavior, but specific mechanisms that connect peripheral immunity with neural circuit function have not been validated. Now, a study published in the July 2016 issue of Nature from a research team lead by Dr. Vladimir Litvak at the University of Massachusetts and Dr. Jonathan Kipnis at the University of Virginia demonstrates a critical role for meningeal interferon-γ (IFN-γ) in mediating both neural function and social behavior (Filiano et al, 2016). Their results suggest that social deficits symptomatic in a variety of neuropsychatric disorders may result from the dysfunctional immune responses altering neural circuit homeostasis.
IFN-γ from meningeal T cells regulates social behavior, elevates GABAergic tone, and reduces hyper-excitability in prefrontal cortex neurons
The group first investigated social behavior in mice devoid of a functional adaptive immune system. C57BL/6J-SCID mice (B6.CB17-Prkdcscid/SzJ; 001913) mice were tested in a three-chamber sociability test, which measures social motivation by quantifying time spent investigating a novel object versus another conspecific mouse. Wild-type mice preferentially investigated the mouse over the object, whereas the SCID mice did not show a social preference. Further studies demonstrated that the reduced sociability demonstrated by the SCID mice was not due to increased anxiety or to either motor or olfactory deficits that might have impacted their performance. Interestingly, when the 4-week-old, immune-deficient SCID mice were repopulated with lymphocytes from wild-type donors, their social preferences increased to the level of the wild-type group.
A gene set enrichment analysis used to search for the pathways in T cells that might mediate the observed social behavior strongly implicated IFN-γ-related genes. IFN-γ knockout mice (B6.129S7-Ifngtm1Ts/J; 002287) showed social deficits and non-anxious behavior similar to the SCID mice. Further, repopulating SCID mice with lymphocytes from IFN-γ knockout donors did not restore the treated animals’ social preferences to wild-type levels. A single injection of recombinant IFN-γ into the cerebrospinal fluid of IFN-γ knockout mice, however, restored the animals’ social preferences by 24 hours post-injection. In contrast, social deficits in IFN-γ receptor knockout mice (B6.129S7-Ifngr1tm1Agt/J; 003288) were not reversed by injection of IFN-γ into the CSF.
Microglia were excluded as the IFN-γ source mediating social behaviors in mice, because mice with cre-recombinase mediated, microglia-specific deletion of STAT1,a signaling molecule downstream of IFN-γ, did not show social deficits. (Monocyte-specific, STAT1-deficient mice were produce from crossing B6J.B6N(Cg)-Cx3cr1tm1.1(cre)Jung/J (025524) and B6;129S-Stat1tm1Mam/Mmjax (012901) mice.)
A final series of experiments investigated the mechanism by which IFN-γ could mediate the social behavior. Deficits in social behavior were observed in mice with deletion of STAT1 from inhibitory gamma-Aminobutyric acid (GABA) neurons (a cross between STOCK Slc32a1tm2(cre)Lowl/J; 016962, and B6;129S-Stat1tm1Mam/Mmjax; 012901), suggesting that the IFN-γ may be signaling through inhibitory neural circuitry. To investigate this further, acute brain slice preparations from wild-type mice were treated with IFN-γ, and inhibitory GABAergic currents in the prefrontal cortex were measured. IFN-γ increased GABAergic currents in wild-type mice. Moreover, in vivo injection of IFN-γ into the cerebrospinal fluid of wild-type mice reduced susceptibility to seizures induced with the GABA type A receptor antagonist pentylenetetrazole. Treatment with diazepam, a benzodiazepine that augments GABAergic neurotransmission, also rescued social behavior in IFN-γ receptor knockout mice.
These results suggest that social deficits derived from IFN-γ deficiency may be linked to a concomitant loss of GABAergic neuron-mediated synaptic inhibition.
These data suggest a novel role for IFN-γ signaling in mediating social behavior via GABAergic signaling in the prefrontal cortex. Interestingly, genetic mutations that impact GABAergic signaling are associated with neurological disorders with dysfunctional behavioral phenotypes, including autism spectrum disorders, Prader-Willi syndrome, and Angelman syndrome. Social proximity certainly increases vulnerability to infections, as anyone who frequents airports or daycare centers can attest. A better understanding of these mechanisms may not only illuminate a compelling natural history linking our social proclivities with immune system ontology, but may also identify possible therapeutic targets for correcting impaired social behaviors manifest in a variety of neurodevelopmental and neuropsychatric disorders.
Filiano AJ, Xu Y, Tustison NJ, Marsh RL, Baker W, Smirnov I, Overall CC, Gadani SP, Turner SD, Weng Z, Peerzade SN, Chen H, Lee KS, Scott MM, Beenhakker MP, Litvak V, Kipnis J. 2016. Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour. Nature. Jul 21;535(7612):425-9. PMID: 27409813.