The Development of Facial Motor Neuron Subtypes in Health and in Congenital Facial Weakness

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PROJECT SUMMARY Aberrant changes in mature neural connections and their function can be induced by infection and inflammation within the brain. The intracellular protozoan parasite, Toxoplasma gondii, is one pathogen that infects the brain, evokes a prolonged inflammatory response and can cause seizures. Persistent infection by this parasite is also associated with behavioral alterations and is a considerable risk factor for developing psychiatric illness, includ- ing schizophrenia. Over 30% of Americans are presently living with an incurable long-term infection of Toxo- plasma gondii, yet, despite its prevalence and implications for serious neurological disorders, we lack sufficient understanding of the effect of life-long parasitic infection on the brain – a major organ of the human body in which the parasite invades cells. This study seeks to elucidate the underlying mechanisms of brain circuitry dysregu- lation in long-term infection in response to this unmet need. Our recent studies have revealed that Toxoplasma gondii brain infection causes changes in inhibitory circuitry (specifically the loss of inhibitory synapses) along with changes in inhibitory neurotransmission, leading to the onset of seizures. Moreover, preliminary studies demonstrating increased expression of classical complement cascade components, elevated microglial activa- tion, and substantial microglial ensheathment of neurons and inhibitory nerve terminals, propose dynamic inter- active roles for the innate immune system and resident-macrophages of the brain in altering functionally mature neural circuits during parasitic infection. In this proposal, we test the hypotheses that molecular components of the innate complement pathway mediate inhibitory synapse loss and seizures, and that microglia remove and phagocytose these synapses following chronic Toxoplasma gondii infection. By capitalizing on multi-scale imag- ing modalities, the aims in this proposal will deliver novel ultrastructural and real-time insight into the impact of chronic parasitic infection on mature neural circuits and will offer a novel mechanism as to how persistent Toxo- plasma gondii infection may contribute to both seizures and psychiatric illness. This study is directly aligned with the NIH's Blueprint Program's mission to expand our understanding of the neuroimmune dynamic interactions that give way to neurological disorders.