Chronic Toxoplasma gondii Infection Results in Elevated Matrix Metalloproteinase-9 and Reduced Cerebellar Perineuronal Nets

Matrix Metalloproteinase-9 (MMP-9) is essential for regulating and organizing perineuronal nets (PNN), which are specialized extracellular matrix (ECM) structures, by cleaving and degrading ECM components. PNNs have neuroprotective capacities and participate in signal transduction, controlling neuronal activity and plasticity. Synaptic plasticity is considered to be the basis for learning and memory. Brain infection by the parasite Toxoplasma gondii impairs learning and memory, although the underlying mechanisms remain largely unknown. We examined the roles of MMP-9 and PNN in a mouse model with chronic infection. 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. MMP-9 expression was notably associated with the loss of PNNs. There was a trend toward a negative correlation between MMP-9 and aggrecan expression, a critical component of PNN. A significant increase in the synaptic vesicle protein synaptophysin was observed, consistent with the role of PNN reduction, which decreases inhibitory activity. Our findings suggest that tissue cysts are crucial for the elevation of MMP-9 expression, leading to the degradation of PNN essential for synaptic plasticity. These findings provide a possible mechanism for Toxoplasma-associated deficits in learning and memory.