A screen of immune signaling molecules regulated by neuronal activity identifies interferon-gamma as a modulator of synaptic function and anxiety-like behavior.

A number of immune signaling molecules have been shown to act within the central nervous system to regulate neuronal function. To look for additional candidates, we conducted a screen of the expression of immune signaling molecules regulated by neuronal activity in the hippocampus. Hippocampal slice cultures were treated for 48 h with TTX (to block neuronal activity) or gabazine (to block GABA-A receptors and thus elevate neuronal activity). These treatments are known to trigger homeostatic synaptic plasticity, and regulate the expression of the pro-inflammatory cytokine tumor necrosis factor alpha (TNF). The screen revealed a number of immune signaling molecules were upregulated by TTX, and a smaller subset upregulated by gabazine. We validated some of the more prominent responders, including Interferon gamma (IFNγ). We then tested the effects of IFNγ on synaptic function. IFNγ could acutely alter both glutamatergic and GABAergic synaptic function, and mice with deficient IFNγ signaling have altered anxiety-like behaviour, although only in males. These data support the idea that many signaling molecules initially characterized in the immune system have important endogenous regulatory roles within the CNS under non-pathological conditions.