Elevated matrix Metalloproteinase-9 associated with reduced cerebellar perineuronal nets in female mice with toxoplasmosis

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Brain infection by the parasite Toxoplasma gondii is thought to impair learning and memory, although the underlying mechanisms remain largely unknown. Recent studies suggest that perineuronal nets (PNNs) and their key regulator, matrix metalloproteinase-9 (MMP-9), have essential roles in synaptic plasticity associated with learning and memory. We investigated their roles in a chronic toxoplasmosis model using female mice. In mice with a high parasite burden of chronic infection, we found that MMP-9 expression was increased in the peripheral circulation and the brain. A correlation was found between the serum levels of MMP-9 and antibodies to the Toxoplasma matrix antigen MAG1, a surrogate marker for Toxoplasma tissue cysts in the brain. MMP-9 elevation was accompanied by increased expression of its endogenous regulators, TIMP-1 and NGAL. An increase in the levels of GSK-3α/β was observed, alongside a decrease in inhibitory GSK-3α/β (Ser-21/Ser-9) phosphorylation. MMP-9 expression was notably associated with the loss of PNNs but increased expression of the synaptic vesicle protein synaptophysin. There was a trend toward a negative correlation between MMP-9 and aggrecan expression, a critical PNN component. Together, these results suggest that chronic Toxoplasma infection can cause an increase in MMP-9 expression, resulting in the degradation of PNNs, which provides a possible mechanism for Toxoplasma-associated deficits in learning and memory.