Topics in Pediatric Neurology: ASD and NF1. Hayley Drozd

Transcription

1 Topics in Pediatric Neurology: ASD and NF1 Hayley Drozd

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3 Autism u Prevalence: 1/68 children u 4:1 male to female preference u 6:1 mild; 1.7:1 moderate-severe u Male: externalizing; Female: internalizing u 3 pillars: communication, social, stereotypic u Spectrum of symptoms u Range of intelligence, social motivation, stereotypy, communication skills (receptive/expressive) u Many comorbidities

4 Autism comorbidities u Epilepsy u Sleep disorders u GI/nutrition problems u Immune dysfunction u Anxiety (girls) u ADHD (boys) u OCD

5 Screening and Diagnosis u Screening behaviors: u Stereotypic behaviors u Repetitive toy movements rather than play, hand flapping, sensory sensitivities u Communication u Verbal milestones, respond to name u Social u Diagnosis: u Smile when smiled at; cuddles; joint attention (look direction parent is looking/pointing); does not pretend play u ADOS or AOSI u Multidisciplinary: rule out other causes such as PKU, speech disorder, behavior disorder, child abuse, etc

6 Early detection: Eye-tracking: Geo preference Test Specificity and positive predictive value of the Geo Pref Test were considerably high (98% and 90% respectively) April 11, 2015 in Biological Psychiatry by Karen Pierce and colleagues contained 444 subjects sampled from the general population and is the largest eye tracking study of ASD to date

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9 What causes autism? u Immune regulation: u Chronic low-level inflammation in the brain; high activity of microglia u Microbiome u Risk with maternal autoimmune disorders u Brain Development: u Overstimulation of sensory circuitry: persistent activity u Different expression of synaptic proteins u Altered development in key brains areas: u Amygdala, Prefrontal cortex, Superior temporal gyrus u Quick early development, low later development of the brain u Genetic/Environmental: u Genetic risk factors: immune system, cell cycle regulators, OXTR, GAD1, RELN, EN2, and ENO2 u Epigenetic modifications: ZFP57 and MECP2 u Sex hormones/oxytocin expression/receptors

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11 How can we study ASD? Genetic models of particular behaviors

12 How can we study ASD? Genetic models of particular behaviors

13 What is neurofibromatosis? u Nf1 u More common u 1 of every 2,500 births u ½ spontaneous mutations, auto dominant u café-au-lait spots, lisch nodules, neurofibromas u NF2 u 1 in 25,000 births u Tumors often on bilateral vestibular schwannomas, affect hearing/balance

14 NF1 Clinical Features u Often diagnosed by age 8, typically will express clinically no later than age 20

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17 Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21- activated kinase u Children with Neurofibromatosis type 1 (NF1) are increasingly recognized to have high prevalence of social difficulties and autism spectrum disorders (ASD). We demonstrated selective social learning deficit in mice with deletion of a single Nf1 gene (Nf1 +/ ), along with greater activation of mitogen activated protein kinase pathway in neurons from amygdala and frontal cortex, structures relevant to social behaviors. The Nf1 +/ mice showed aberrant amygdala glutamate/gaba neurotransmission; deficits in long-term potentiation; and specific disruptions in expression of two proteins associated with glutamate and GABA neurotransmission: a disintegrin and metalloprotease domain 22 (ADAM22) and heat shock protein 70 (HSP70), respectively. All of these amygdala disruptions were normalized by codeletion of p21 protein-activated kinase (Pak1) gene. We also rescued the social behavior deficits in Nf1 +/ mice with pharmacological blockade of Pak1 directly in the amygdala. These findings provide novel insights and therapeutic targets for NF1 and ASD patients.

18 Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21- activated kinase u Children with Neurofibromatosis type 1 (NF1) are increasingly recognized to have high prevalence of social difficulties and autism spectrum disorders (ASD). We demonstrated selective social learning deficit in mice with deletion of a single Nf1 gene (Nf1 +/ ), along with greater activation of mitogen activated protein kinase pathway in neurons from amygdala and frontal cortex, structures relevant to social behaviors. The Nf1 +/ mice showed aberrant amygdala glutamate/gaba neurotransmission; deficits in long-term potentiation; and specific disruptions in expression of two proteins associated with glutamate and GABA neurotransmission: a disintegrin and metalloprotease domain 22 (ADAM22) and heat shock protein 70 (HSP70), respectively. All of these amygdala disruptions were normalized by codeletion of p21 protein-activated kinase (Pak1) gene. We also rescued the social behavior deficits in Nf1 +/ mice with pharmacological blockade of Pak1 directly in the amygdala. These findings provide novel insights and therapeutic targets for NF1 and ASD patients.

19 Claims u Nf1 model shows autism-like behavior: social memory u NF1 pathway is overactive in amygdala and prefrontal cortex u Long term potentiation is deficient u Protein expression of synaptic proteins is deficient u Pak1 deletion both GENETICALLY and PHARMACOLOGICALLY rescues autism behavior

20 Claims u Nf1 model shows autism-like behavior: social memory u NF1 pathway is overactive in amygdala and prefrontal cortex u Long term potentiation is deficient u Protein expression of synaptic proteins is deficient u Pak1 deletion both GENETICALLY and PHARMACOLOGICALLY rescues autism behavior

21 How to measure autism in a mouse: Day 1 Day 2 Familiar Familiar 1 st Novel Familiar Familiar 2 nd Novel Video - 10 min Video - 10 min Video - 10 min 45 min (no video) Video - 10 min Habituation Familiarization Short Term Social Memory (Familiar & novel mouse) Acclimation (Familiar mouse) Long-Term Social Learning (Familiar & new, novel mouse)

22 Social/non-social Behavior/Memory

23 Anxiety/depression/olfaction

24 Claims u Nf1 model shows autism-like behavior: social memory u NF1 pathway is overactive in amygdala and prefrontal cortex u Long term potentiation is deficient u Protein expression of synaptic proteins is deficient u Pak1 deletion both GENETICALLY and PHARMACOLOGICALLY rescues autism behavior

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26 Claims u Nf1 model shows autism-like behavior: social memory u NF1 pathway is overactive in amygdala and prefrontal cortex u Long term potentiation is deficient u Protein expression of synaptic proteins is deficient u Pak1 deletion both GENETICALLY and PHARMACOLOGICALLY rescues autism behavior

27 Social v. other behaviors

28 Claims u Nf1 model shows autism-like behavior: social memory u NF1 pathway is overactive in amygdala and prefrontal cortex u Long term potentiation is deficient u Protein expression of synaptic proteins is deficient u Pak1 deletion both GENETICALLY and PHARMACOLOGICALLY rescues autism behavior

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30 Claims u Nf1 model shows autism-like behavior: social memory u NF1 pathway is overactive in amygdala and prefrontal cortex u Long term potentiation is deficient u Protein expression of synaptic proteins is deficient u Pak1 deletion both GENETICALLY and PHARMACOLOGICALLY rescues autism behavior

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32 Claims u Nf1 model shows autism-like behavior: social memory u NF1 pathway is overactive in amygdala and prefrontal cortex u Long term potentiation is deficient u Protein expression of synaptic proteins is deficient u Pak1 deletion both GENETICALLY and PHARMACOLOGICALLY rescues autism behavior

33 Previous: whole Pak1 KO; now targeted

34 Future directions/ How to improve study u Is there a competing fear response going on? u Is this behavior a measure of fear or of autism? u Adverse effects of robust Pak1 inhibition? -> u All the trials done in male mice u Don t girls have autism too? u One behavior was different u Are there any other behaviors that could be good paradigms in this NF1 model? u The NF1 cascade is involved. The amygdala is involved. u What types of neurons are involved?

35 Future directions/how to improve study u Is there a competing fear response going on? u Is this behavior a measure of fear or of autism? u Adverse effects of robust Pak1 inhibition? u All the trials done in male mice u Don t girls have autism too? u One behavior was different u Are there any other behaviors that could be good paradigms in this NF1 model? u The NF1 cascade is involved. The amygdala is involved. u What types of neurons are involved?

36 Optogenetics

37 How can we use optogenetics?

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39 Implications u u u u u Comorbidities with developmental disorders impacts quality of life for patients NF1 can be used to study ASD Pak1 inhibitor could be a drug candidate Optogenetics: basic science u It s pretty cool! u Learn specific networks/protein expression Optogenetics: Clinical Application u Similar concept to deep brain stimulating procedures u Epilepsy, Parkinson s, Huntington s u More specific: only target key cells, less side effects u DRUGS

40 Links to References u u u u pdf