Astrocytic NLRP3 cKO Mitigates Cognitive Impairment Induced by Paclitaxel in Mice

Chemotherapy-induced cognitive impairment (CICI) is a prevalent and debilitating sequela in cancer patients receiving paclitaxel. Our previous study revealed that glial cells, particularly astrocytes, regulate NLRP3-mediated neuroinflammation, which is crucial to the pathophysiology of cognitive deficits. However, the therapeutic potential of targeting astrocytic NLRP3 for CICI remains largely unexplored. This study sought to determine whether astrocyte-specific NLRP3 knockout (KO) could mitigate paclitaxel-induced cognitive impairment. A mouse model of CICI was established via intraperitoneal injection of paclitaxel. Cognitive function was assessed using the Morris water maze and novel object recognition tests. Immunofluorescence labelling and local field potential (LFP) recordings in the medial prefrontal cortex (mPFC) were used to analyze pathological changes. Astrocyte-specific NLRP3 KO reduced intensities of GFAP, decreased colocalization of cleaved caspase-1 and IL-18 with astrocytes. Besides, the deletion approach significantly mitigated paclitaxel-induced cognitive deficits and increased the expression of synaptic markers, including synaptophysin and postsynaptic density protein 95 (PSD95). Electrophysiologically, astrocytic NLRP3 deletion improved the power of β- and γ-band oscillations and enhanced β-γ phase-amplitude coupling during novel object exploration. Astrocyte-specific NLRP3 knockout confers a protective effect against paclitaxel-induced cognitive dysfunction, potentially through inhibition of NLRP3 inflammasome-mediated pyroptotic signaling in astrocytes and preservation of synaptic integrity within the mPFC.