Transcript The Neurotropic Parasite Toxoplasma Gondii Increases Domapine

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
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. 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
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 mocktreated 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)