Hippocampal HMGB1/TLR4 activation elevates KYNA levels and contributes to novel-object recognition dysfunction in LPS-treated mice
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Updated: Nov 4, 2026
Immunohistochemical Visualization of Hippocampal Neuron Activity After Spatial Learning in a Mouse Model of Neurodevelopmental Disorders
Published on: May 12, 2015
Ting Liu1, Siyi Han1, Xiaoyu Zhang1
1Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Background:
Neuroinflammation is a major contributor to cognitive dysfunction, yet the mechanisms linking inflammatory signaling to synaptic dysfunction remain incompletely understood. Kynurenic acid (KYNA), an endogenous metabolite derived from tryptophan catabolism, modulates neuronal and synaptic activity, yet its involvement in neuroinflammation-associated cognitive dysfunction remains largely unexplored.
Methods:
A lipopolysaccharide (LPS)-induced neuroinflammation mouse model was established to evaluate recognition memory, synaptic plasticity, and molecular changes in the hippocampus. KYNA levels and KAT2 expression were assessed, along with HMGB1/TLR4 signaling activity. Pharmacological interventions using a KAT2 inhibitor (PF04859989) and an HMGB1 antagonist (glycyrrhizic acid) were applied to dissect the mechanistic pathway.
Results:
LPS administration induced robust neuroinflammation, increased KYNA production, and impaired novel object recognition. These changes were accompanied by reduced expression of NMDAR subunits (NR2A and NR2B), decreased levels of synaptic proteins (PSD95 and vGluT1), impaired long-term potentiation, and reduced sEPSC frequency. Inhibition of KAT2 lowered KYNA levels and restored synaptic function and recognition-memory performance without affecting HMGB1/TLR4 signaling. In contrast, HMGB1 blockade suppressed neuroinflammation, decreased KAT2 expression and KYNA production, and improved synaptic plasticity.
Conclusions:
These findings identify an HMGB1/TLR4-KAT2/KYNA-synapse axis linking neuroinflammation to recognition-memory impairment. KYNA, which is primarily synthesized in astrocytes, acts as a key downstream effector mediating synaptic dysfunction, highlighting KYNA metabolism as a potential therapeutic target for neuroinflammation-associated recognition-memory impairment.
