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The Neurotropic Parasite Toxoplasma Gondii Increases Domapine Metabolism. By Emese Prandovsky , Elizabeth Gaskell, Heather Martin, J.P. Dubey , Joanne P. Webster, Glenn A. McConkey. Presented by Julia Gray. T. Gondii.
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The Neurotropic Parasite Toxoplasma Gondii Increases Domapine Metabolism By EmesePrandovsky, Elizabeth Gaskell, Heather Martin, J.P. Dubey, Joanne P. Webster, Glenn A. McConkey Presented by Julia Gray
T. Gondii • Parasite – an organism that lives on or in an organism of another species, known as the host, from the body of which it obtains nutriment • Common global protozoan parasite • Requires both definitive host and intermediate host to complete its life cycle • Cats are the only definitive host • Any warm blooded animal can • be affected • 25% of popluation (over 12)
Key Words • Bradyzoites – slowly replicating versions of the parasite • Tachyzoites – motile asexually reproducing form of the parasite • PC12 Cells – Dopamine producers • Immunofluorescence – technique used for light microscopy with a florescence microscope. Uses the specificity of antibodies to their antigen • Glyoxylic acid – reacts with catecholamines to form florescent products
Effects In Rodents • During chronic stage of infection rodents exhibit a distinctive set of behavioral changes • Loss of aversion to cat odors • Conversely attracted to these odors • Specific to feline odor • Similar change is not evoked by other predators and has no effect on conditioned fear and aniety • Mechanisms for this phenomena are currently unknown
Experiment • Used immunofluorescence to monitor the process of infection in mice • Infected the brain with tachyzoites • Probed with dopamine antibody (Abcam) which was stained • Localization was primarily within the T. gondiitissue cysts
Experiment • Dopamine detected in T. gondiitissue cysts • Could this affect neurotransmission? • Tested the effect of T. gondii infection on dopamine release from dopminergic neural cells in vitro • Took PC12 cells (dopamine producers) and infected them with T. gongii • Dopamine content and release were monitored
Results • Infected cultures accumulated significantly greater levels of dopamine and the increase correlated with infection rate • 3 fold increase in total dopamine content compared to mock-treated uninfected cells
Tyrosine Hydroxylase • Rate-limiting enzyme in dopamine • Significant levels of tyrosine hydroxylase were localized within T. gondii tissue cysts in the brain sections of infected mice • T. gondii could provide an enzyme with tyrosine hydroxylase activity (TgTh) • Encoded TgTh that could be expressed in the brain tissue cysts • To specifically identify parasite-encoded tyrosine hydroxylase they created a custom antibody • Target sequence at amino terminal (unique and different from mammalian)
Results • T. gondii tyrosine hydroxylase was localized within tissue cysts in chronically infected brains • T. gondii both inducing the synthesis of dopaine and producing limiting enzyme
Discussion • Mechanism for change in behavior is closely linked to dopamine • Encysted T. gondiihave been observed in functional neurons with intact synapses • Tissue cysts all throughout the brain • Higher in amygdala and nucleus accumbens • Control of movements (vassal ganglia), reward to stimuli, pleasure, dependency (nucleus accumbens and hippocampus), motivation and cognition, stimuli specific fear
Significance • Affect in humans • Lasts throughout the lifetime of the host • Association between T. gondiiseroprevalence with schizophrenia • Dopamine dysreulation is proposed to play a central role in schizophrenia • Possibly in combination with glutamate metabolism • The principal antipsychotic drug that has been used to treat schizophrenia (dopamine antagonist haloperidol, can also block the development of behavior changes in T. gondii infected rodents • Dopamine dysfunction has been associated with a variety of neurological disorders (schizophrenia, ADHD, tic disorders, Tourette’s, dykinesias)