Targeted rescue of synaptic plasticity improves cognitive decline in sepsis-associated encephalopathy.
Mol Ther
; 32(7): 2113-2129, 2024 Jul 03.
Article
em En
| MEDLINE
| ID: mdl-38788710
ABSTRACT
Sepsis-associated encephalopathy (SAE) is a frequent complication of severe systemic infection resulting in delirium, premature death, and long-term cognitive impairment. We closely mimicked SAE in a murine peritoneal contamination and infection (PCI) model. We found long-lasting synaptic pathology in the hippocampus including defective long-term synaptic plasticity, reduction of mature neuronal dendritic spines, and severely affected excitatory neurotransmission. Genes related to synaptic signaling, including the gene for activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) and members of the transcription-regulatory EGR gene family, were downregulated. At the protein level, ARC expression and mitogen-activated protein kinase signaling in the brain were affected. For targeted rescue we used adeno-associated virus-mediated overexpression of ARC in the hippocampus in vivo. This recovered defective synaptic plasticity and improved memory dysfunction. Using the enriched environment paradigm as a non-invasive rescue intervention, we found improvement of defective long-term potentiation, memory, and anxiety. The beneficial effects of an enriched environment were accompanied by an increase in brain-derived neurotrophic factor (BDNF) and ARC expression in the hippocampus, suggesting that activation of the BDNF-TrkB pathway leads to restoration of the PCI-induced reduction of ARC. Collectively, our findings identify synaptic pathomechanisms underlying SAE and provide a conceptual approach to target SAE-induced synaptic dysfunction with potential therapeutic applications to patients with SAE.
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Assunto principal:
Fator Neurotrófico Derivado do Encéfalo
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Proteínas do Citoesqueleto
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Modelos Animais de Doenças
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Disfunção Cognitiva
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Encefalopatia Associada a Sepse
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Hipocampo
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Plasticidade Neuronal
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article