Synaptic Signaling Mechanisms in Toxoplasma Infected Brains

The protozoan parasite Toxoplasma gondii infects approximately one-third of the world’s population. Most people are asymptomatic because the parasite resides latently within the brain and other tissues. But AIDS and other immunosuppressed patients as well as fetuses are in danger of developing toxoplasmosis when the parasite reactivates and the host immune response is unable to control parasite replication or is dysregulated. When reactivation occurs in the brain, toxoplasmic encephalitis can develop and present with a variety of neurological complications that includes seizures. Why patients develop seizures is unclear but in other encephalopathies 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. And, how these changes in the brain alter synaptic wiring and neurotransmission that cause epileptiform activity is largely unknown. Data from a murine toxoplasmic encephalitis model reveal that onset of seizures is associated with three events – increased interleukin-1 signaling, increased excitatory neurotransmission, and ensheathment and subsequent loss of inhibitory perisomatic synapses. The work proposed here will seek to understand how loss of inhibitory perisomatic synapses occurs. In Aim 1, we will study how the complement system recognizes the inhibitory synapses to be eliminated and in Aim 2 we will identify the factor(s) that neurons express to recruit microglia that remove these synapsesAddressing and answering these questions will increase our understanding of how pathogen-host cell interactions lead to seizures and will inform future work aimed at generating novel therapies to treat these patients . Project Number: 1R01NS148151-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Ira Blader | Institution: VIRGINIA POLYTECHNIC INST AND ST UNIV, BLACKSBURG, VA | Award Amount: $392,338 | Activity Code: R01 | Study Section: Clinical Neuroimmunology and Brain Tumors Study Section[CNBT] View on NIH RePORTER: https://reporter.nih.gov/project-details/11339134