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 Medicine Baltimore, Maryland
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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
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
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
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
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
Male Female0
102030405060708090
100
% C
ued
food
/tot
al
ControlPRU
Sex-dependent cognitive impairment Social transmission of food preference
Xia, Kannan et al, 2012
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
Schizophrenia is a Developmental Disorder
(Jaaro-Peled et al., TINS, 2009)
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