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

• Auto-antibodies to NMDA receptors

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