Defining neuronal subtypes and electrophysiological properties of Toxoplasma gondii interacted neurons

University Of Arizona, Tucson AZ

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Abstract

Abstract: Toxoplasmai gondii is a neurotropic intracellular parasite that causes a life-long latent infection by encysting in the brain. T. gondii?s ability to asymptomatically persist within the central nervous system (CNS) is quite unu- sual, leading some investigators to investigate how this chronic infection might change baseline physiology. These investigations have been limited to understanding global changes, such as global neurotransmitter re- lease or electrophysiology via electroencephalography as no mechanism existed to interrogate in vivo how T. gondii might change infected neurons. At the single cell level only one in vitro study demonstrated hyper and hypoexcitable states of neuron firing, but even this study failed to look at the individual neuron. We have over- come this barrier by developing a novel mouse model that allows us to permanently mark and track CNS host cells that have been injected with parasite effector proteins, parasite proteins that are secreted into host cells and manipulate host cells processes. In addition, because the marking of these cells is only dependent on the injection of a T. gondii protein and does not require an active infection, we can identify injected host cells, even if these cells do not harbor parasites. Using this novel system, we have determined that: i) T. gondii persists in neurons because parasites primarily interact with neurons; ii) the vast majority of these T. gondii-injected neu- rons (TINs) (~95%) do not harbor parasites; and iii) TINs are not homogenously distributed throughout the brain. Based upon these findings and prior work, I hypothesize, therefore, that neurons injected with T. gondii effector proteins will be significantly changed such that they will show altered physiology. Given how widely neuron physiology can vary by region and neuron subtype, we have used a stepwise approach. First, we used a MATLAB-based mapping program to determine that the isocortex and striatum are enriched for TINs. Within these regions, I have used immunofluorescence assays to identify specific neuron subtypes that are targeted by T. gondii. Based upon these findings, I am now determining how the electrophysiology of TINs differ from bystander neurons of the same subtype in the same region of the brain.