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

Abstract

Sepsis-associated encephalopathy (SAE) is a major and frequent complication in patients with sepsis resulting in delirium and premature death. Sepsis survivors commonly suffer from long-term cognitive impairment causing immense burden on patients, caregivers, and economic health systems. The underlying pathophysiology of SAE is largely unresolved, thus treatment options are missing. We report that experimental polymicrobial sepsis in mice induces synaptic pathology in the central nervous system underlying defective long-term potentiation and cognitive dysfunction. Analysis of differentially expressed genes revealed severely affected downregulation of genes related to neuronal and synaptic signaling in the brain, e.g. of the activity-regulated cytoskeleton-associated protein (Arc), of the transcription-regulatory EGR family, and of the dual-specificity phosphatase 6 (Dusp6). On the protein level, ARC expression and mitogen-activated protein (MAP) kinase signaling in the brain was disturbed during SAE. For targeted rescue of dysregulated synaptic signaling and plasticity, we overexpressed ARC in the hippocampus by bilateral in-vivo stereotactic microinjection of an adeno-associated virus containing a neuron-specific plasmid of the Arc transgene. Hereby, defective synaptic plasticity and signaling in the hippocampus were restored and memory function improved. Accordingly, 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 of long-term cognitive dysfunction. 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.

Microglia mediate neurocognitive deficits by eliminating C1q-tagged synapses in sepsis-associated encephalopathy

“…On days 8 to 10, meropenem was applied every day. Thereafter, to avoid reoccurring systemic infection at later stages, enrofloxacin (Baytril 2.5%; Bayer AG, Germany) was added to the drinking water of sham-and PCI-treated animals with saccharose added in a final concentration of 2 mg/ml until the end of the experiment (54).…”

Neurofilament light chains to assess sepsis-associated encephalopathy: Are we on the track toward clinical implementation?

“…Interestingly, these findings in humans are corroborated in murine sepsis models and mechanistic analyses showed disordered neuronal transmission and brain network function together with neuronal damage, loss of dendritic spines and synapses as well as microglia activation [46][47][48][49][50][51][52][53]. As a consequence, specific learning and memory tasks, e.g., object recognition and spatial memory, are impaired in post-septic mice [49,53,54].…”

Repopulated microglia after pharmacological depletion decrease dendritic spine density in adult mouse brain

“…For each gene, the p-value was calculated using the Wald signifi- An arm entry was defined by all four feet being set in the respective arm. The EPM was cleaned using 70% ethanol after each trail to ensure equal experimental conditions (Grünewald et al, 2021). 3 | RESULTS…”