kannan and pletnikov
TRANSCRIPT
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Toxoplasma gondii and cognitive deficits in schizophrenia:an animal model perspective
G. Kannan and M. Pletnikov
Departments of Psychiatry and Behavioral Sciences, Neuroscience, Molecular and Comparative Pathobiology
Johns Hopkins University School of MedicineBaltimore, Maryland
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Animal models of mental disease
• Replicating psychiatric symptoms is a daunting task
• Animal model needs to address the specific question
• Various approaches
– Using etiologically relevant environmental and/or genetic risk factors to better understand the underlying neurobiology of psychiatric disease
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Animal models of T. gondii infection
• A microbial pathogen relevant to schizophrenia
• Many infections have species-specific mechanisms and pose challenges for animal models
• T. gondii infection likely involves the similar mechanisms in humans and animals
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Cognitive deficits in schizophrenia • Least amenable to treatment
• Learning and memory tests to study cognitive impairment – Translational potential vs. other tests– Similar underlying biology
• Synaptic pathology
• Complexity of T. gondii effects on cognition – Please, see Table in our review for diversity of effects
• Type or strain of T. gondii• Sex-dependent effects • Time of infection
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T. gondii strain-related cognitive deficit
Control PRU ME490
10203040506070
*
% o
f alte
rnati
ons
Control PRU ME4952
54
56
58
60
62
64
Tim
e (s
ec)
Working memory Spatial recognition
Kannan et al, 2010
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Male Female0
102030405060708090
100
% C
ued
food
/tot
al
ControlPRU
Sex-dependent cognitive impairment Social transmission of food preference
Xia, Kannan et al, 2012
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Time-dependent disruption of pre-pulse inhibition
Pre-pulse levels
p4 p8 p12 p16 p200
20
40
60
80 DPBSPRU
*
% o
f PPI
p4 p8 p12 p16 p200
1020304050607080
ControlPRU
Juvenile
Adult
Kannan et al, prelim data
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Schizophrenia is a Developmental Disorder
(Jaaro-Peled et al., TINS, 2009)
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Targeting glutamatergic synapses • Effects of pro-inflammatory factors on glutamatergic synaptic
neurotransmission
• Major histocompatibility complex class I (MHCI) molecules in neuroplasticity
• Decreased expression of NMDA receptors on GABA neurons as a result of GABA neurons dysfunction due to neuroinflammation
• Elevated levels of KYNA to antagonize NMDA receptors
• Auto-antibodies to NMDA receptors
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Acknowledgements
Pletnikov lab
Geetha KannanChunxia Yang
Bagrat Abazyan Alexey Shevelkin Meng Xia Sofya Abazyan Michelle Potter Fabrice Casseus Joshua Crawford
The Stanley Division at Hopkins
Robert Yolken Lori Brando J-C Xiao Emily Severance Sarven Sabunciyan
JHU Schizophrenia Conte Center
Akira Sawa
Supported by the Stanley Medical Research Institute, NIMH