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- 1. Exploring the Neurobiology of Down Syndrome: From Science to Medicine Center for Down Syndrome Research and Treatment University of California, San Diego
- 2. The Investigators Mike Pavel Alexander Ahmad Chengbiao
- 3. Steve Wagner
- 4. v OUR BOSSES
- 5. Discover genes and mechanisms Create treatments Define the problems Deliver treatments THE PLAN THE BOSS
- 11. X X Hypothesis Extra Gene(s) Abnormal Synapses Cognitive Problems Research Strategy Cognitive Phenotype Treatment Gene(s) &/or Mechanism
- 12. APP Grik1 Sod1 Gart Sim2 Dryk1a Ets2 Mx1 Sod1 Gart Sim2 Dryk1a Mx1 Ets2 APP Grik1 Sod1 Ts65Dn Ts1Cje Ms1Ts65 A Mouse Model of Down Syndrome Gabpa
- 13. Defining the Genetic Basis for Cognitive Deficits in Mouse Models of Down Syndrome
- 15. Inhibition Is Excessive This Produces and Imbalance In E/I Ratio + _ - + Glutamate GABA
- 16. Excitatory and Inhibitory Synapses in 2 N versus Ts65Dn Mice 0.5 m b
- 17. Array Tomography Methodology: Micheva et al 2007
- 18. Evidence for Increased Inhibition Disrupting Plasticity PP PP
- 19. Defining the Genetic Basis for Cognitive Deficits in Mouse Models of Down Syndrome
- 20. Hypothesis Extra Gene(s) Abnormal Synapses Cognitive Problems Research Strategy Cognitive Phenotype Treatment Gene(s) &/or Mechanism Abnormal Learning & Memory Inc. Inhibition Treat Inc. Inhibition
- 23. Neurotrophic Factor Signals Are Critical for Survival and Maintenance of Neurons And The Circuits In Which They Work Signaling Endosomes Carry Trophic Signals
- 24. PP Sch MF CA1 A lv CA3 Entorhinal Cortex 1 2 3 Cortex DG BFCN DGC Perforant Path Raphe Locus Defining A Role For Neurotrophic Factors in Hippocampal Circuits Dysfunction in Down Syndrome APP Gene Dose Plays A Role
- 27. Impact of Increased APP Gene Dose: Focus on Processing APP
- 28. Hypothesis Extra Gene(s) Abnormal Synapses Cognitive Problems Research Strategy Cognitive Phenotype Treatment Gene(s) &/or Mechanism Age-Related Abnormal Learning & Memory APP Gene Dose & Degeneration Decrease APP, Modify Processing, or Restore Connections
- 33. Acknowledgements Supported by: -Down Syndrome Research and Treatment Foundation -National Institutes of Health -Larry L Hillblom Foundation -Thrasher Foundation -Alzheimer’s Association -Cure Alzheimer’s Fund
Notas do Editor
- Elements of the Center. Define the most significant cognitive problems facing individuals with DS. Uses mouse models to phenocopy these problems, maps the critical genes and their mode of actions and then, together with industry, find effective treatments that can make a difference.
- Elements of the Center. Define the most significant cognitive problems facing individuals with DS. Uses mouse models to phenocopy these problems, maps the critical genes and their mode of actions and then, together with industry, find effective treatments that can make a difference.
- Fig 2. AT methodologies. A. AT imaging achieves superlative resolution and depth-independence of sensitivity based on planar arraying, staining and imaging of physical sections. B. The AT proteomic imaging cycle involves multiple rounds of immunostaining, imaging, and antibody elution, allowing collection of data from up to at least 40 antibody channels in a single ribbon of sections at full resolution.
- This schematic diagram shows a crosscut of the hippocampus of the mouse brain. The hippocampus is selectively affected in people with Down syndrome. The hippocampus is much involved in the processing of information leading to learning and memory. The hippocampus has a circuit that consists of three neurons, each of which is excitatory. The circuit is activated by input from the entorhinal cortex and sends its information from the hippocampus back to the cortex. Neurons from the entorhinal cortex send their axons through the perforant pathway (green line) to hippocampus. Their axons synapse with the granule cells of the dentate gyrus (red neuron). The granule cells send their axons to synapse with pyramidal cells (black) lying in the CA3 region of the hippocampus. Finally, the pyramidal cells in the CA3 region send axons to synapse on the pyramidal cells (black) in the CA1 region. This three neuron circuit is important for learning and encoding and memory.