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 Universit
y 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
Developmental stage
Genetic factors
Environmental stimuli
Epigenetic factors
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Reciprocal connection between the immune system
and ASD
Immune system abnormalities in autism
Immune responses associated with 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

• Congenital rubella infection
• MMR vaccination??

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What is the link between the immune system and
ASD?
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Two brain peptides are associated with ASD
Oxytocin
Vasopressin
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SON and PVN magnocellular neurons
Ludwig and Leng 2006
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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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Zymosan A-initiated peritonitis
Time (h)
Real-time PCR analysis of OTR expression
0
4
Tissue and serum collection
Animals sacrificed
Zymosan A injection
24
ELISA analysis of serum oxytocin level
72
Chemokines Clearance during Resolution
CCL2
15
CXCL8
10
CXCL2
ng/mouse
5
0
0
24
48
72
2
12
4
Time (h)
chemokine clearance
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Peritonitis elevates oxytocin receptor
transcription in the male mouse brain
Transcripts relative to Male 0h
Time following injection
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Oxytocin receptor transcription in the brain is
elevated by peritonitis in males but not in
females
Transcripts relative to 0 hr
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Peritonitis elevates serum oxytocin levels
Serum oxytocin (Pg/ml)
Time following injection
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Where in the brain?
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Elevation of oxytocin receptor transcription in
the brain is region-specific
Transcripts relative to Male 0 hr
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
Negative feedback mechanisms
Inflammation
Baseline
Genetic background Developmental stage
Chronic depression
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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
Dr. Sagie Schiff