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Autism Susceptibility

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by impaired communication, social interaction, and repetitive behaviors. With a diagnosis rate of 1 in 110 children, it predominantly affects boys, with a male-to-female ratio of 4:1. Factors contributing to ASD are multifactorial, including genetic susceptibilities (e.g., SHANK2, HOXA1), environmental influences (toxic exposure, dietary factors), and immunological responses. Early detection and intervention are crucial in supporting children with ASD, highlighting the importance of understanding genetic and developmental factors.

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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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