Toxoplasma gondii Regulation of Host GABAergic Signaling

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 DESCRIPTION (provided by applicant): Seizures are a common and life-threatening complication of individuals suffering from infections and inflammation in the central nervous system. In these individuals, seizures develop due to a variety of reasons including breakdown of the blood-brain barrier, changes in ionic homeostasis, and/or increased abundance of inflammatory proteins such as cytokines and antibodies. But, how these changes in the brain alter synaptic wiring and neurotransmission that cause epileptiform activity is largely unknown. The protozoan parasite Toxoplasma gondii infects approximately one-third of the world's population. Most people are asymptomatic because the parasite resides latently within brain and other tissues. But individuals who are immunocompromised or are infected in utero develop toxoplasmosis when the parasite reactivates and the host immune response is unable to control parasite replication or is dysregulated leading immune-mediated tissue destruction. If reactivation occurs in the brain, the resulting toxoplasmic encephalitis presents with a variety of neurological sequelae that includes seizures. Using a murine model for toxoplasmic encephalitis our data indicates that Toxoplasma specifically alters the distribution of key proteins that localie to GABAergic synapses. This change in GABAergic synaptic connectivity causes the mice to develop seizures because these synapses are critical for controlling the flow and timing of information transfer in the brain. This work will define how these proteins are mislocalized (Aim 1), determine the role of inflammatory cells in GABAergic protein mislocalization (Aim 2), and identify the parasite factors that affect GABAergic protein localization and onset of seizures (Aim3). The long-term goal of this work is to determine how seizures develop in Toxoplasma-infected individuals and use this information to generate novel therapies to treat these patients and others suffering from infection-induced seizures.