The Neurotropic Parasite Toxoplasma Gondii Increases Domapine Metabolism

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. GONDIIParasite – 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. gondii

tissue cysts

EXPERIMENT• Dopamine detected in T. gondii tissue 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

RESULTSInfected 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. gondii have 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. gondii seroprevalence 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)