The Role of IFN-γ and STAT1 Signaling in Neuronal Excitability and Behavior

Abstract

The IFN-γ/STAT1 response is an immune signaling pathway well known for its potent pro-inflammatory and anti-viral functions. However, IFN-γ/STAT1 signaling also impacts many homeostatic and pathological aspects in the central nervous system, beyond its canonical role in controlling intracellular pathogens. IFN-γ can modulate neuronal excitability, synaptic pruning, and gene expression of pathways associated with neurodevelopmental disorders, including autism spectrum disorder (ASD) and schizophrenia (SZ). Surprisingly, the IFN response was recently identified as the most highly enriched pathway in brains of individuals with ASD and SZ. Children born to mothers who are hospitalized for infection during pregnancy are at a higher risk of developing ASD, and mouse models demonstrate that elevating cytokines during embryonic neurodevelopment cause ASD-like phenotypes. While microglia are thought to be the major targets of IFNs in the brain, neurons can respond to IFNs and require physiological levels of IFN-γ for proper function. The IFN-γ/STAT1 pathway is rapidly activated then deactivated to prevent excessive inflammation; however, neurons utilize unique IFN-γ/STAT1 activation patterns, which may contribute to the non-canonical neuron-specific downstream effects. We hypothesized that pathological IFN-γ signaling in neurons leads to neuronal dysfunction and behavioral deficits through non-canonical STAT1 signaling. Using primary neuron cultures, we demonstrated that developing neurons have differential STAT1 activation downstream of physiological versus pathological IFN-γ. Physiological levels of IFN-γ caused brief and transient STAT1 activation, while high pathological levels of IFN-γ caused robust and prolonged activation of STAT1 in neurons, but not in microglia or astrocytes. To determine the effects of prolonged STAT1 activation in vivo, we developed a novel mouse model in which STAT1 signaling is prolonged in neurons. These mice displayed hyperactive behavior and neural hypoactivity, which are common comorbidities of neurodevelopmental disorders like ASD and attention deficit hyperactivity disorder (ADHD). Moreover, we demonstrated that this phenotype is neuron specific, as mice with prolonged STAT1 activation in microglia did not have behavior deficits. Our findings suggest pathological activation of the IFN-γ/STAT1 pathway contributes to neuronal dysfunction through non-canonical STAT1 activation. Overall, the IFN-γ/STAT1 pathway is critical for normal neurodevelopment and neuronal function in adulthood and provides new insight into a neuron specific neuroimmune mechanism which may contribute to the pathophysiology of neurodevelopmental disorders.