Neonatal NLRP3 Inflammasome Activation Leads to Perineuronal Net Deficits in Early Adulthood.

Perineuronal nets (PNNs) are specialized extracellular matrix structures that surround certain neurons and play a critical role in protecting neurons from oxidative stress and maintaining synaptic stability in the central nervous system. They have roles in memory formation, and their loss has been linked to various mental alterations, such as anxiety, depression, and schizophrenia. While immune activation is known to degrade PNNs, it remains unclear whether inflammasomes are involved in PNN formation dynamics during neuronal development, where cases of sepsis are particularly high. In this study, we investigated how activation of the NLRP3 inflammasome in neonatal mouse brains influences PNNs. To explore this, neonatal wild-type and Nlrp3 knockout mice were injected with lipopolysaccharide (LPS) or phosphate-buffered saline (PBS) on postnatal day (PND) 9, and PNNs were visualized at early adulthood (PND60). In addition, NLRP3 inflammasome activation was confirmed on PND10, and behavioral tests were performed on PND60. LPS treatment in wild-type mice reduced PNN-positive neurons in the hippocampus and cortex compared to the PBS group, whereas Nlrp3 knockout mice showed no differences between treatment groups. Moreover, behavioral tests revealed that neonatal LPS injection resulted in anxiety- and depressive-like behavior and that NLRP3 deficiency restrained this effect. These results highlight the key role of NLRP3 inflammasome activation in inflammation-driven PNN reduction during neuronal development. NLRP3 inhibitors could thus serve as potential therapeutic agents to protect the neuronal extracellular matrix from inflammatory damage in early life.