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?

Oxytocin Vasopressin

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/m

ouse

0

5

10

15

CXCL2

CCL2

CXCL8

0 24 48 722

Time (h)chemokineclearance

124

Zymosan A-initiated peritonitis

Time (h)04

24

72

Animals

sacrificed

Real-time PCR

analysis of OTR

expression

ELISA

analysis of serum

oxytocin level

Tissue and

serum

collection

Zymosan A

injection

0.00

20.00

40.00

60.00

80.00

100.00

0 hr 4 hr 24 hr 72 hr ATLa 4 hr

Peritonitis elevates oxytocin receptor

transcription in the male mouse brain

Tra

nsc

rip

ts r

elat

ive

to M

ale

0h

Time following injection

0.00

20.00

40.00

60.00

80.00

100.00

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

Oxytocin receptor transcription in the brain is

elevated by peritonitis in males but not in females

Tra

nsc

rip

ts r

elat

ive

to 0

hr

0.00

50.00

100.00

150.00

200.00

250.00

0 hr 4 hr 24 hr 72 hr ATLa 4 hr

Peritonitis elevates serum oxytocin levelsSe

rum

oxy

toci

n (

Pg/

ml)

Time following injection

Where in the brain?

0.00

4.00

8.00

12.00

16.00

20.00

24.00

28.00

cerebellum olfactory bulb frontal lobe parietal lobe temporal lobe subcorticalareas

Tra

nsc

rip

ts r

elat

ive

to M

ale

0 h

rElevation 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

Inflammation

Dr. Sagie Schiff

Dr. Amiram ArielDr. Efra Edri

Dr. Hala Harony

Sharon Inberg

Amir Cyjon

Hadar Shachar-gold

Lilach Porat

Guy Shpak

Dana Shamama

Sharon Rustami

Michal Bar