Reduced inhibitory and excitatory input onto parvalbumin interneurons mediated by perineuronal net might contribute to cognitive impairments in a mouse model of sepsis-associated encephalopathy

• Published in: Neuropharmacology 2023-03, Vol.225, p.109382-109382, Article 109382
• Main Authors: Zhang, Ling, Gao, Yu-Zhu, Zhao, Chun-Jie, Xia, Jiang-Yan, Yang, Jian-Jun, Ji, Mu-Huo
• Format: Article
• Language: English
• Subjects: Animals; Cognitive Dysfunction - metabolism; Cognitive impairments; Interneurons - physiology; Lipopolysaccharide; Lipopolysaccharides - toxicity; Matrix Metalloproteinase 9; Mice; Parvalbumin interneuron; Parvalbumins - metabolism; Perineuronal net; Sepsis-Associated Encephalopathy - metabolism
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2022.109382

Sepsis-associated encephalopathy (SAE) is commonly defined as diffuse brain dysfunction and can manifest as delirium to coma. Accumulating evidence has suggested that perineuronal net (PNN) plays an important role in the modulation of the synaptic plasticity of central nervous system. We here investigated the role of PNN in SAE induced by lipopolysaccharide (LPS) injection. Behavioral tests were performed by open field, Y-maze, and fear conditioning tests at the indicated time points. The densities of vesicular γ-aminobutyric acid transporter, vesicular glutamate transporter 1, PNN, and parvalbumin (PV) in the hippocampus were evaluated by immunofluorescence. Matrix metalloproteinases-9 (MMP-9) expression and its activity were detected by Western blot and gel zymography, respectively. Local field potential was recorded by in vivo electrophysiology. LPS-treated mice displayed significant cognitive impairments, coincided with activated MMP-9, decreased PNN and PV densities, reduced inhibitory and excitatory input onto PV interneurons enwrapped by PNN, and decreased gamma oscillations in hippocampal CA1. Notably, MMP-9 inhibitor SB-3CT treatment rescued most of these abnormalities. Taken together, our study demonstrates that active MMP-9 mediated PNN remodeling, leading to reduced inhibitory and excitatory input onto PV interneurons and abnormal gamma oscillations in hippocampal CA1, which consequently contributed to cognitive impairments after LPS injection. [Display omitted] •The density of PNN+ and PV+ cells were decreased in hippocampal CA1 in SAE mice.•SAE mice displayed cognitive impairments and abnormal gamma oscillation.•The reduction of PNN was associated with MMP-9 activation.•MMP-9 inhibitor SB-3CT reversed most of above abnormalities.