Kannan and Pletnikov

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presentation made by Dr. Misha Pletnikov November 13, 2012 on the Schizophrenia Research Forum (www.schizophreniaforum.org).

presentation made by Dr. Misha Pletnikov November 13, 2012 on the Schizophrenia Research Forum (www.schizophreniaforum.org).

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  • 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. AcknowledgementsPletnikov labGeetha KannanChunxia YangBagrat AbazyanAlexey ShevelkinMeng XiaSofya AbazyanMichelle PotterFabrice CasseusJoshua CrawfordThe Stanley Division at HopkinsRobert YolkenLori BrandoJ-C XiaoEmily SeveranceSarven SabunciyanJHU Schizophrenia Conte CenterAkira Sawa Supported by the Stanley Medical Research Institute, NIMH