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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
– Spectrum: low to high cognitive function• Autism, PDD, Rett’s disorder, child disintegrative disorder, and
Asperger’s disorder
Pediatrics (2004) 113:472-486
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
Causation
• Single factor vs Multifactor• Development vs Plasticity
Developmental Factors
• TAOK2 – Impaired dendrite formation
• Abnormal connectivity (hyper & hypo connectivity)
Nature Neuro, 2012; 15(7): 1022-1033
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!
Causation
• Single factor vs Multifactor• Development vs Plasticity
Synaptic Plasticity and Transmission
• NMDA activation or CAMKII activation leads to AMPA trafficking
Synapse Formation
PSD Scaffolding
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)
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
PSD Scaffolding
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
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
SHANK2 and ASD
• Generated a SHANK-/- mouse– Role in behavior– Synaptic transmission (LTP/LTD)
SHANK-/- mice
• PDZ removal via exon 6/7 excision – Found in ASD and ID human populations
• Did not reduce number of neurons
SHANK-/- Mice Social ImpairmentsImpaired social interaction in home cage
Preference to objects over social
SHANK-/- Mice Speech Impairments
SHANK-/- Mice Repetitive Behaviors
Repetitive Jumping Behavior
Repetitive Grooming Behavior
Repetitive Digging Behavior
SHANK -/- hyperactivity
SHANK -/- memory and learning impairments
SHANK -/- mice
• Decreased Social engagement• Learning Impairments• Decreased vocalizations• Hyperactivity• Repetitive behaviors and selective interests
Synaptics
• Impaired LTP and LTD – Schaffer collateral-CA1 pyramidal synapses– Induced via high or low frequency stimulation
NMDA/AMPA Ratio
Recovery of NMDA/AMPA ratio with D- cycloserine (NMDA-R partial agonist)
D-cycloserine social impairment rescue
CDPPB rescues synaptics and behavior
• Membrane-permeable positive allosteric modulator of mGluR5– Increases mGluR5 responsiveness to glutamate– Enhances NMDA-R function
CDPPB rescues social behavior
Synaptic Plasticity and Transmission
• NMDA activation or CAMKII activation leads to AMPA trafficking
CDPPB does not rescue…
• Repetitive behaviors and hyperactivity not rescued• Did not report CDPPB Morris water maze or vocalization tests!
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
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