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Kannan and Pletnikov
- 1. 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
- 2. 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
- 3. 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
- 4. 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
- 5. T. gondii strain-related cognitive deficit Working memory Spatial recognition 80 80 % of alternations 60 * 60 Time (sec) 40 40 20 20 0 0 Control PRU ME49 Control PRU ME49 Kannan et al, 2010
- 6. Sex-dependent cognitive impairment Social transmission of food preference 120 100 Control % Cued food /total PRU 80 60 40 20 0 Male Female Xia, Kannan et al, 2012
- 7. Time-dependent disruption of pre-pulse inhibition 80 DPBS PRU Juvenile 60 40 * 20 % of PPI 0 p4 p8 p12 p16 p20 80 Control Adult 60 PRU 40 20 0 p4 p8 p12 p16 p20 Pre-pulse levels Kannan et al, prelim data
- 8. Schizophrenia is a Developmental Disorder (Jaaro-Peled et al., TINS, 2009)
- 9. 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
- 10. Acknowledgements Pletnikov lab Geetha Kannan Chunxia 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
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