Guanabenz Reduces Hyperactivity and Neuroinflammation Caused by Latent Toxoplasmosis in Mice

Abstract

Toxoplasma gondii is an intracellular parasite that causes persistent, lifelong infection in one-third of humans worldwide. The parasite converts from a lytic, actively replicating form (tachyzoite) into a latent tissue cyst form (bradyzoite) that evades host immunity and is impervious to current drugs. While acute infection can be life threatening to immunosuppressed individuals, chronic infection has been linked to behavioral changes in rodents and neurological disease in humans. Notably, chronic infection in mice leads to hyperactivity in an open field. Whether these behavioral changes are due to parasite manipulation of the host or the host response to infection remains an outstanding question. We have previously shown that the anti-hypertensive drug guanabenz reduces Toxoplasma cyst burden in the brains of BALB/c mice, providing a means to examine whether brain cyst depletion reverses behavioral changes. We used two mouse strains (BALB/c and C57BL/6) differing in their susceptibility to infection. Following drug treatment of chronically infected mice, locomotor activity in an open field was assessed. In both mouse strains, the increased hyperactivity seen during chronic infection returned to normal levels following guanabenz treatment. Guanabenz reduced brain cyst burden ~70% in BALB/c mice as expected, but it increased cyst burden 49% in C57BL/6 mice. Examination of the brains showed that guanabenz decreased inflammation and perivascular cuffing in both infected mouse strains. Our study shows for the first time that it is possible to reverse a key behavioral change associated with chronic Toxoplasma infection. Surprisingly, the rescue from parasite-induced hyperactivity correlates with a decrease in neuroinflammation instead of cyst counts, suggesting that some behavioral changes arise from host responses to infection rather than a parasite-driven process.