Oxytocin receptor as a potential link between the immune system and autism
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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
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Autism Spectrum Disorder (ASD)
Neurodevelopmental disorder characterized mainly by:
» Impairment in social cognition and interactions
» Impairment in verbal communication
» Stereotypical behaviors and repetitive movements
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The prevalence of ASD in the population
is on a rise and is now 0.5-1%
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The etiology of ASD
Genetic factors
Environmental stimuli
Epigenetic factors
Developmental stage
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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??
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What is the link between the
immune system and ASD?
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Oxytocin Vasopressin
Two brain peptides are associated with ASD
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Ludwig and Leng 2006
SON and PVN magnocellular neurons
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Oxytocin in known for its maternity functions
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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
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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
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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.
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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
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0.00
20.00
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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
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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
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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
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Where in the brain?
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0.00
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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
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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
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Oxytocin receptor is a potential link
between the immune system and ASD
Baseline
Chronic depression
Negative feedback
mechanisms
Genetic background
Developmental stage
Inflammation
Inflammation
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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