Autism Susceptibility Autism Neurodevelopmental disorder Impaired communication social
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 (HOXA 1, FOXp 2, DBH, Me. CP 2, NLGN 3, NLGN 4, NRN 1, FMR 1, SHANK 2, TAOK 2 – 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 • TAOK 2 – 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
SHANK 2 • Function: molecular scaffolds in the PSD – Contains multiple domains for protein/protein interaction: • • Ankyrin repeats SH 3 domain PSD-95 domain PDZ domain (specific to SHANK 2)
SHANK 2 and Synaptogenesis • May play role in synaptogenesis via: – Attaching m. Glu. Rs to existing pool of NMDA-Rs by linking NMDA-Rs through PSD-95 and m. Glu. Rs through HOMER 1 – HOMER/SHANK/GKAP/PSD-95 assembly mediates physical association of NMDA-Rs with IP 3 R/RYR and intracellular calcium stores
PSD Scaffolding
Susceptibility gene? • Shank 2 variants found in BOTH control population and ASD population • ASD population has significantly more conserved Shank variants PLo. S Genet 8(2): e 1002521
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
SHANK 2 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 Impairments Impaired 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-CA 1 pyramidal synapses – Induced via high or low frequency stimulation
NMDA/AMPA Ratio Recovery of NMDA/AMPA ratio with Dcycloserine (NMDA-R partial agonist)
D-cycloserine social impairment rescue
CDPPB rescues synaptics and behavior • Membrane-permeable positive allosteric modulator of m. Glu. R 5 – Increases m. Glu. R 5 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 • m. Glu. R 5 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 SHANK 2) – Critical Period – Early intervention: therapy, special education, home enrichment, pharmacological approaches • Children with same mutation but different home life vary in cognitive function • Susceptibility – SHANK 2 Mutations without ASD • At risk for having ASD children • Environmental factors
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