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Oxytocin receptor as a potential link between the immune system and autism

Oxytocin receptor as a potential link between the immune system and autism. Shlomo Wagner Department of Biology and Department of Neurobiology and Ethology The Lab for Neurobiology of Social Communication University of Haifa, Israel. Autism Spectrum Disorder (ASD).

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Oxytocin receptor as a potential link between the immune system and autism

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  1. Oxytocin receptor as a potential link between the immune system and autism Shlomo Wagner Department of Biology and Department of Neurobiology and Ethology The Lab for Neurobiology of Social Communication University of Haifa, Israel

  2. Autism Spectrum Disorder (ASD) Neurodevelopmental disorder characterized mainly by: • Impairment in social cognition and interactions • Impairment in verbal communication • Stereotypical behaviors and repetitive movements

  3. The prevalence of ASD in the population is on a rise and is now 0.5-1%

  4. The etiology of ASD Developmental stage Genetic factors Environmental stimuli Epigenetic factors

  5. Reciprocal connection between the immune system and ASD Immune system abnormalities in autism Immune responses associated with autism • Decreased peripheral lymphocytes numbers • Decreased response to T cell mitogens • Incomplete or partial T cell activation • Imbalance of serum Ig levels • Anti-brain autoantibody production • Increased proinflammatory cytokines • Congenital rubella infection • MMR vaccination??

  6. What is the link between the immune system and ASD?

  7. Two brain peptides are associated with ASD Oxytocin Vasopressin

  8. SON and PVN magnocellular neurons Ludwig and Leng 2006

  9. Oxytocin in known for its maternity functions

  10. Oxytocin receptor localization in the mouse brain (partial list) • Olfactory bulb • Anterior olfactory nucleus • Piriform cortex • Entorhinal cortex • Multiple amygdala nuclei • Multiple hypothalamic nuclei • Parasubiculum • Vestibular nucleus • Facial nucleus • Nucleus of solitary tract

  11. Oxytocin has a central role in mammalian social behavior 1. Oxytocin receptor distribution in the brain determines monogamy in voles 2. Oxytocin- and oxytocin receptor-knockout mice are specifically impaired in their social behavior 3. Oxytocin sniffing enhances social cognition and trust in humans

  12. Oxytocin is implicated in ASD • Plasma oxytocin levels in boys with autism were found to be lower than in a group of age-matched controls. • Intravenous infusion of oxytocin to adults with ASD resulted in a reduction in repetitive behaviors and facilitated the processing and retention of social information. • Multiple genetic studies support a genetic association between polymorphism in the oxytocin receptor gene and ASD.

  13. Zymosan A-initiated peritonitis Real-time PCR analysis of OTR expression Time (h) 0 4 Tissue and serum collection Animals sacrificed Zymosan A injection 24 ELISA analysis of serum oxytocin level 72 Chemokines Clearance during Resolution CCL2 15 CXCL8 10 CXCL2 ng/mouse 5 0 4 12 24 48 72 0 2 Time (h) chemokine clearance

  14. Peritonitis elevates oxytocin receptor transcription in the male mouse brain Transcripts relative to Male 0h Time following injection

  15. Oxytocin receptor transcription in the brain is elevated by peritonitis in males but not in females Transcripts relative to 0 hr

  16. Peritonitis elevates serum oxytocin levels Serum oxytocin (Pg/ml) Time following injection

  17. Where in the brain?

  18. Elevation of oxytocin receptor transcription in the brain is region-specific Transcripts relative to Male 0 hr Brain region

  19. Conclusions • Oxytocin receptor transcription in the brain is elevated during peritonitis. • This elevation is male-specific and brain-region specific. • It is accompanied by elevation in serum oxytocin levels

  20. Oxytocin receptor is a potential link between the immune system and ASD Inflammation Negative feedback mechanisms Inflammation Baseline Genetic background Developmental stage Chronic depression

  21. Dr. Amiram Ariel Dr. Efra Edri Dr. Hala Harony Sharon Inberg Amir Cyjon Hadar Shachar-gold Lilach Porat Guy Shpak Dana Shamama Sharon Rustami Michal Bar Dr. Sagie Schiff

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