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