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%

Genetic factors

The etiology of ASD

Developmental stage Environmental stimuli Epigenetic factors

Reciprocal connection between the immune system and ASD 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

Immune responses associated with autism

• • Congenital rubella infection MMR vaccination??

What is the link between the immune system and ASD?

Two brain peptides are associated with ASD Oxytocin Vasopressin

SON and PVN magnocellular neurons

Ludwig and Leng 2006

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.

Zymosan A-initiated peritonitis

Zymosan A injection Time (h) 0 4 24 Animals sacrificed Tissue and serum collection

Real-time PCR

analysis of OTR expression

ELISA

analysis of serum oxytocin level 72

15 10

Chemokines Clearance during Resolution CCL2 CXCL8 CXCL2

5 0 0 2 4

chemokine clearance

12 24

Time (h)

48 72

100.00

Peritonitis elevates oxytocin receptor transcription in the male mouse brain 80.00

60.00

40.00

20.00

0.00

0 hr 4 hr 24 hr Time following injection 72 hr ATLa 4 hr

Oxytocin receptor transcription in the brain is elevated by peritonitis in males but not in females 100.00

80.00

60.00

40.00

20.00

0.00

Male 0 hr Male 4 hr Female 0 hr Female 4 hr

Peritonitis elevates serum oxytocin levels 250.00

200.00

150.00

100.00

50.00

0.00

0 hr 4 hr 24 hr Time following injection 72 hr ATLa 4 hr

Where in the brain?

Elevation of oxytocin receptor transcription in the brain is region-specific 28.00

24.00

20.00

16.00

12.00

8.00

4.00

0.00

cerebellum olfactory bulb frontal lobe parietal lobe temporal lobe Brain region subcortical areas

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 Inflammation

Baseline

Genetic background Developmental stage Negative feedback mechanisms Inflammation

Chronic depression

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