Transcript Induction of the autism related oxytocin receptor in the

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
Developmental
stage
Genetic
factors
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 receptorknockout 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
Time (h)
Real-time PCR
0
4
analysis of OTR
Tissue and
Animals
Zymosan A
24
serum
sacrificed
injection
expression
collection
ELISA
analysis of serum
oxytocin level
72
Chemokines Clearance during Resolution
CCL2
15
ng/mouse
CXCL8
10
CXCL2
5
0
0
2 4
12
chemokine
clearance
24
Time (h)
48
72
Peritonitis elevates oxytocin receptor
transcription in the male mouse brain
Transcripts relative to Male 0h
100.00
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
Transcripts relative to 0 hr
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
Serum oxytocin (Pg/ml)
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
Transcripts relative to Male 0 hr
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 subcortical
areas
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
Negative feedback
Inflammation
mechanisms
Inflammation
Baseline
Genetic background
Developmental stage
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