The Abnormal Synaptic Perisomatic Input Onto Parvalbumin Interneurons Mediated By Hipppocampal Perineuronal Net Might Contribute To Cognitive Impairment Induced By Neuroinflammation

Objective:Neuroinflammation is a prominent pathological feature in the progression of a wide range of neurodegenerative diseases and is considered to be one of the main causes of cognitive impairment.However,precisely how neuroinflammation leads to cognitive impairment remains unclear.Perineuronal net(PNN)is a special type of extracellular matrix,which mainly surrounds soma and proximal dendrites of parvalbumin interneuron(PV).PNN plays an important role in controlling the plasticity of central nervous system.However,the changes and roles of PNN and PV remain largely unknown in the neuroinflammation.Therefore,the present study aimed to investigate the role of PNN and PV in neuroinflammation-related cognitive dysfunction induced by the intraperitoneal injection of the bacterial endotoxin lipopolysaccharide(LPS),one of the most important and widely-used animal models of peripherally induced neuroinflammation,and explore the potential mechanism.Methods:Part one: adult male C57BL/6 mice were randomly divided into two groups(n = 13-15): saline group(Control group)and lipopolysaccharide group(LPS group).Intraperitoneal injection of lipopolysaccharide 2 mg/kg was used to establish neuroinflammation animal model.The control mice received the same dose of saline.The intensity of Iba1,CD68 and GFAP and PNN/PV density in the hippocampus were evaluated by immunofluorescence.MMP-9 expression and activity were detected by Western blot and gel zymography.Part two: adult male C57BL/6 mice were randomly divided into four groups(n = 13-15): Group Control + Vehicle,Group Control + SB-3CT,Group LPS + Vehicle,Group LPS + SB-3CT.The method of modeling is the same as above.SB-3CT was injected intraperitoneally at 25 mg/kg 30 minutes before LPS injection and 24 hours after LPS injection.Immunofluorescence technology was used to detect the MMP-9 cell location,PV/PNN density and fluorescence intensity and synaptic input onto PV cells surrounded by PNN.Open field test was conducted to evaluate the locomotor activity of mice.Y-maze and fear conditioning test were conducted to assess cognitive function.Results:Compared with the control group,the intensity of Iba1,CD68 and GFAP were significantly increased in the hippocampus in LPS mice,indicating that intraperitoneal injection of LPS can induce hippocampal neuroinflammation;meanwhile the expression and activity of MMP-9 were increased and the density of PNN and PV positive cells were decreased in the hippocampal CA1 region after lipopolysaccharide challenge(P< 0.05).Notably,SB-3CT can inhibit the activity of MMP-9 and effectively prevent the decrease in the number of PNN-positive cells and PNN expression in the hippocampal CA1 area(P< 0.05),but it had no significant effect on the decreased number of PV-positive cells(P> 0.05).Compared with the group Control +Vehicle,the spontaneous alternation in the Y maze test and freezing time in the fear conditioning test were significantly reduced,the inhibitory and excitatory perisomatic input onto parvalbumin interneurons surrounded by PNN were significantly reduced in group LPS+Vehicle(P< 0.05).Compared with the group LPS+Vehicle,the spontaneous alternation in the Y maze test and freezing time in the fear conditioning test were significantly increased,the inhibitory and excitatory perisomatic input onto parvalbumin interneurons surrounded by PNN were significantly increased in group LPS + SB-3CT(P< 0.05).Conclusion: The results suggest that LPS-induced neuroinflammation mediates PNN remodeling in the hippocampal by activating MMP-9,leading to abnormal inhibitory and excitatory perisomatic synaptic input onto PV interneurons surrounded by PNN and cognitive impairment.The selective MMP-9 inhibitor SB-3CT can effectively reduce the abnormal synaptic input of PV neurons surrounded by PNN and improve cognitive function by inhibiting the degradation of PNN.