Astrocytic NLRP3 cKO mitigates depression-like behaviors induced by mild TBI in mice.

Reports indicate that depression is a common mental health issue following traumatic brain injury (TBI). Our prior research suggests that Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-related neuroinflammation, modulated by glial cells such as astrocytes, is likely to play a crucial role in the progression of anxiety and cognitive dysfunction. However, there is limited understanding of the potential of astrocytic NLRP3 in treating depression under mild TBI condition. This study aimed to determine whether astrocytic NLRP3 knockout (KO) could mitigate depressive-like behaviors following mild TBI and explore potential variations in such behaviors between genders post-mild TBI. Mild TBI was induced in mice using Feeney's weight-drop method. Behavioral assessments included neurological severity scores (NSS), social interaction test (SI), tail suspension test (TST), and forced swimming test (FST). Pathological changes were evaluated through immunofluorescence and local field potential (LFP) recordings at various time points post-injury. Our findings indicated that astrocyte-specific NLRP3 KO decreased cleaved caspase-1 colocalized with astrocytes, decreased pathogenic astrocytes and increased Postsynaptic density protein 95 (PSD95) intensity, and significantly alleviated mild TBI-induced depression-like behaviors. It also led to the upregulation of protective astrocytes and apoptosis-associated factors, including cleaved caspase-3 post-mild TBI. Additionally, astrocyte-specific NLRP3 deletion resulting in improved θ and γ power and θ-γ phase coupling in the social interaction test (SI). Notably, under mild TBI conditions, astrocyte-specific NLRP3 exhibited greater neuroprotective effects in female knockout mice compared to males. Astrocyte NLRP3 knockout demonstrated a protective mechanism in mice subjected to mild TBI, possibly attributed to the inhibition of pyroptosis through the NLRP3 signaling pathway in astrocytes. • TBI induces depression-like behaviors and glial cell activation. • TBI disrupts theta and gamma power and their phase coupling. • The expression of caspase-1 and caspase-3 is higher in astrocytes rather than in microglia after TBI. • Targeting astrocytic NLRP3 shows promise in reducing behavioral symptoms of depression post-mild TBI in mice. • Female mice exhibit enhanced neuroprotective effects with astrocytic NLRP3 knockout, highlighting sex-based therapeutic responses to TBI.