Targeted rescue of synaptic plasticity improves cognitive decline after severe systemic inflammation

Sepsis-associated encephalopathy (SAE) is a frequent complication in patients with severe systemic infection resulting in acute brain dysfunction and incapacitating long-term sequelae. SAE includes delirium, premature death, post-traumatic stress disorder, and major long-term cognitive impairment. The underlying pathophysiology of SAE is largely unresolved and specific treatment options are missing. We induced the peritoneal contamination and infection (PCI) sepsis model in 769 mice and compared these with 259 control mice. We found that experimental sepsis causes synaptic pathology in the brain characterized by severely disordered synaptic plasticity with reduced long-term potentiation, changes in CA1 pyramidal neuron dendritic spines, and behavioral abnormalities indicating cognitive dysfunction. Using electrophysiology, we found reduced frequency of quantal and spontaneous excitatory postsynaptic currents whereas amplitudes of miniature, spontaneous, and evoked excitatory currents were increased, pointing towards a homeostatic synaptic scaling mechanism. Corresponding to dysfunctional excitatory synaptic function we discovered downregulation of genes related to neuronal and synaptic signaling in the brain, including the gene for activity-regulated cytoskeleton-associated protein ( Arc/Arg3.1 ), members of the transcription-regulatory EGR gene family, and the gene for dual-specificity phosphatase 6 ( Dusp6 ). At the protein level, ARC expression and MAP kinase signaling in the brain were affected. For targeted rescue of dysfunctional 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. Hereby we achieved recovery of defective synaptic plasticity in the hippocampal Schaffer collateral-CA1 pathway and improvement of memory dysfunction. Using a different rescue paradigm, PCI mice were subjected to enriched environment providing multiple activating stimuli. Enriched environment led to restoration of disordered long-term potentiation and memory, thus demonstrating the potential for activity-induced improvement. Together, we identified synaptic pathomechanisms of SAE after severe systemic infection and provide a conceptual approach to treat SAE-related disease mechanisms which may be applicable to patients afflicted with SAE. ### Competing Interest Statement The authors have declared no competing interest. * AAV : adeno-associated viruses; BDNF : brain-derived neurotrophic factor aCSF : artificial cerebrospinal fluid Arc/Arg3.1 : activity-regulated cytoskeleton-associated protein AP : anterior-posterior BBB : blood brain barrier BM : Barnes maze CLP : cecal ligation and puncture CREB : cAMP response element-binding protein CSS : Clinical Severity Score CXC : C-X-C motif chemokine ligand DEG : differentially expressed genes Dusp6 : dual-specificity phosphatase 6 DV : dorso-ventral L : lateral EE : enriched environment EGR : early growth response protein EPSC : excitatory postsynaptic currents EPM : elevated plus maze test ERK : extracellular-signal regulated kinase fEPSP : field Evoked Postsynaptic Potential GO : Gene Ontology HBS : HEPES buffered saline IEG : immediate early gene (IEG) Il : interleukin LPS : lipopolysaccharide LCN2 : lipocalin 2 LTP : long-term potentiation NE : not enriched Nrgn : Neurogranin Mapk11 : mitogen-activated protein kinase 11 MWM : morris water maze test OF : open fieled test ORF : Open reading frame PBS : phosphate bufferedsSaline PCI : peritoneal contamination and infection PFA : paraformaldehyde qPCR : quantitative real-time PCR RIS : RNA Integrity Score rsn : robust spline normalization SAE Sepsis-associated encephalopathy SC : Schaffer collateral s.c. : subcutaneous SEM : standard error of the mean TNFα : tumor necrosis factor-α trkB : Tropomyosin receptor kinase TTX : Tetrodotoxin WPRE : Woodchuck Hepatitis Virus Posttranscriptional Regulatory Element