Microglia phagocytosis of PNNs mediates PV-positive interneuron dysfunction and associated gamma oscillations in neuroinflammation-induced cognitive impairment in mice

Abstract

Neuroinflammation, characterized by activation of glial cells, plays a critical role in central nervous system disorders. However, the precise mechanisms of neuroinflammation contributing to cognitive impairment remain elusive. Perineuronal nets (PNNs) are extracellular matrixes that envelop the cell bodies and dendrites of parvalbumin (PV)-positive interneurons and may be mediated by apolipoprotein E (ApoE) gene. To investigate whether disruption of PNNs associated with ApoE is implicated in neuroinflammation-induced cognitive impairment, we established a neuroinflammation model by administering lipopolysaccharides (LPS) at 0.5 mg/kg for 7 consecutive days. Cognitive function was assessed using the open field, Y-maze, and novel object recognition tests, and neural oscillations were also recorded. Furthermore, differentially expressed genes in microglia within the hippocampus were identified through single-cell RNA sequencing analysis. Overexpression of hyaluronan and proteoglycan link protein 1 (Hapln1) and ApoE knockdown were carried out through adeno-associated virus (AAV) injection to C57BL/6J mice and CX3CR1-CreERT2 mice, respectively. It was found that LPS-induced neuroinflammation impaired cognitive function by reducing PNNs and PV-positive interneurons’ outputs, as well as disrupting gamma (γ) oscillations in the hippocampal CA1. Overexpression of Hapln1 was able to restore PV-positive interneurons and γ oscillations, ultimately alleviating the cognitive impairment. Mechanistically, LPS-triggered microglial activation leads to the phagocytosis of PNNs, a process influenced by ApoE. Notably, prevention of PNNs engulfment through targeting microglial ApoE in the CA1 improved cognitive impairment. Collectively, our study suggested that microglial phagocytosis of PNNs plays a key role in neuroinflammation-induced cognitive impairment, which is probably mediated by the ApoE.