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Autism Susceptibility

Autism Susceptibility. Autism. Neuro -developmental disorder Impaired communication, social interaction, empathy, repetitive behavior, restricted interests, ADHD Typical onset/diagnosis at 3 (can be as late as 14) Diagnosis vs onset 1/110 children diagnosed 4:1 boys to girl affected

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Autism Susceptibility

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  1. Autism Susceptibility

  2. Autism • Neuro-developmental disorder • Impaired communication, social interaction, empathy, repetitive behavior, restricted interests, ADHD • Typical onset/diagnosis at 3 (can be as late as 14) • Diagnosis vs onset • 1/110 children diagnosed • 4:1 boys to girl affected • Spectrum: low to high cognitive function • Autism, PDD, Rett’s disorder, child disintegrative disorder, and Asperger’s disorder Pediatrics (2004) 113:472-486

  3. Causation • Causes: Unknown • Genetic: Susceptibility genes (HOXA1, FOXp2, DBH, MeCP2, NLGN3, NLGN4, NRN1, FMR1, SHANK2, TAOK2 • Environmental: Diet (nutrient deficiencies, high fructose corn syrup, , toxic environment (mercury), Thimerosal (maybe), age of parents, acetaminophen • Immunological factors: defective placenta, immature BBB, immune response of mother to infection during pregnancy Journal of Immunotoxicology, 2011; 8(1): 68–79

  4. Causation • Single factor vs Multifactor • Development vs Plasticity

  5. Developmental Factors • TAOK2 • Impaired dendrite formation • Abnormal connectivity (hyper & hypo connectivity) Nature Neuro, 2012; 15(7): 1022-1033

  6. Autism and Dendrite Development • Sign up for Neurobiology of Disease next semester!!!! • Covering this AND… • Parkinson’s, Alzheimer’s, Fragile X, MS, ALS, and MORE!

  7. Causation • Single factor vs Multifactor • Development vs Plasticity

  8. Synaptic Plasticity and Transmission • NMDA activation or CAMKII activation leads to AMPA trafficking

  9. Synapse Formation

  10. PSD Scaffolding

  11. SHANK2 • SHANK2 • Function: molecular scaffolds in the PSD • Contains multiple domains for protein/protein interaction: • Ankyrin repeats • SH3 domain • PSD-95 domain • PDZ domain (specific to SHANK2)

  12. SHANK2 and Synaptogenesis • May play role in synaptogenesis via: • Attaching mGluRs to existing pool of NMDA-Rs by linking NMDA-Rs through PSD-95 and mGluRs through HOMER1 • HOMER/SHANK/GKAP/PSD-95 assembly mediates physical association of NMDA-Rs with IP3R/RYR and intracellular calcium stores

  13. PSD Scaffolding

  14. Susceptibility gene? • Shank2 variants found in BOTH control population and ASD population • ASD population has significantly more conserved Shank variants PLoS Genet 8(2): e1002521

  15. Accounting for sex differences • Shank variants found more frequently in males • Autism 4:1 males • Asperger's 11:1 American Jour of Human Gen (2012) 90: 879–887

  16. SHANK2 and ASD • Generated a SHANK-/- mouse • Role in behavior • Synaptic transmission (LTP/LTD)

  17. SHANK-/- mice • PDZ removal via exon 6/7 excision • Found in ASD and ID human populations • Did not reduce number of neurons

  18. SHANK-/- Mice Social Impairments Impaired social interaction in home cage Preference to objects over social

  19. SHANK-/- Mice Speech Impairments

  20. SHANK-/- Mice Repetitive Behaviors Repetitive Jumping Behavior Repetitive Grooming Behavior Repetitive Digging Behavior

  21. SHANK -/- hyperactivity

  22. SHANK -/- memory and learning impairments

  23. SHANK -/- mice • Decreased Social engagement • Learning Impairments • Decreased vocalizations • Hyperactivity • Repetitive behaviors and selective interests

  24. Synaptics • Impaired LTP and LTD • Schaffer collateral-CA1 pyramidal synapses • Induced via high or low frequency stimulation

  25. NMDA/AMPA Ratio Recovery of NMDA/AMPA ratio with D- cycloserine (NMDA-R partial agonist)

  26. D-cycloserine social impairment rescue

  27. CDPPB rescues synaptics and behavior • Membrane-permeable positive allosteric modulator of mGluR5 • Increases mGluR5 responsiveness to glutamate • Enhances NMDA-R function

  28. CDPPB rescues social behavior

  29. Synaptic Plasticity and Transmission • NMDA activation or CAMKII activation leads to AMPA trafficking

  30. CDPPB does not rescue… • Repetitive behaviors and hyperactivity not rescued • Did not report CDPPB Morris water maze or vocalization tests!

  31. Summary • SHANK-/- KO creates ASD mouse phenotype • mGluR5 or NMDA agonists: • Rescue NMDA/AMP ratio, LTP & LTD, social behavior • Does not rescue: hyperactivity or repetitive behavior

  32. Why does ASD susceptibility matter • Early detection of ASD genes (such as SHANK2) • Critical Period • Early intervention: therapy, special education, home enrichment, pharmacological approaches • Children with same mutation but different home life vary in cognitive function • Susceptibility • SHANK2 Mutations without ASD • At risk for having ASD children • Environmental factors

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