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 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 JumpingRepetitive Jumping Behavior Repetitive GroomingRepetitive Grooming Behavior Repetitive Digging 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