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) Neurodevelopmental disorder characterized mainly by: » Impairment in social cognition and interactions » Impairment in verbal communication » Stereotypical behaviors and repetitive movements

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

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

Immune system abnormalities in 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 Reciprocal connection between the immune system and ASD Immune responses associated with autism Congenital rubella infection MMR vaccination??

What is the link between the immune system and ASD?

OxytocinVasopressin Two brain peptides are associated with ASD

Ludwig and Leng 2006 SON and PVN magnocellular neurons

Oxytocin in known for its maternity functions

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

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

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.

Chemokines Clearance during Resolution ng/mouse CXCL2 CCL2 CXCL Time (h) chemokine clearance 124 Zymosan A-initiated peritonitis Time (h) Animals sacrificed Real-time PCR analysis of OTR expression ELISA analysis of serum oxytocin level Tissue and serum collection Zymosan A injection

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

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

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

Where in the brain?

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

Conclusions 1.Oxytocin receptor transcription in the brain is elevated during peritonitis. 2.This elevation is male-specific and brain-region specific. 3.It is accompanied by elevation in serum oxytocin levels

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

Dr. Sagie Schiff 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