Targeted rescue of synaptic plasticity improves cognitive decline in sepsis-associated encephalopathy

Abstract Sepsis-associated encephalopathy (SAE) is a severe and frequent complication in patients with systemic infection resulting in delirium, premature death, and long-term cognitive impairment. The underlying pathophysiology of SAE is largely unresolved and treatment options are missing. We report that experimental sepsis in mice induces synaptic pathology in the brain underlying defective long-term potentiation and cognitive dysfunction. Genes related to neuronal and synaptic signaling in the brain, e.g. the activity-regulated cytoskeleton-associated protein (Arc/Arg3.1), the transcription-regulatory EGR family, and the dual-specificity phosphatase 6 (Dusp6) were downregulated. On the protein level, ARC expression and mitogen-activated protein (MAP) kinase signaling in the brain were affected during SAE. For targeted rescue of dysregulated synaptic signaling and plasticity we overexpressed ARC in the hippocampus by microinjection of an adeno-associated virus containing a neuron-specific plasmid of the ARC transgene. Defective synaptic plasticity in the hippocampus was restored and memory improved. Moreover, synaptic plasticity, neuronal spine pathology, and memory dysfunction also improved when post-septic mice were subjected to enriched environment demonstrating the potential for activity-induced recovery. Together, we identified synaptic pathology of neurocognitive dysfunction after severe systemic infection and provide a proof-of-concept approach to interfere with SAE pathomechanisms leading to cognitive improvement.