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Publication
The Gain-of-Function Integrin ß3 Pro33 Variant Alters the Serotonin System in
the Mouse Brain.
Authors Dohn MR, Kooker CG, Bastarache L, Jessen T, Rinaldi C, Varney S, Mazalouskas MD,
Pan H, Oliver KH, Velez Edwards DR, Sutcliffe JS, Denny JC, Carneiro AMD
Submitted By Submitted Externally on 12/5/2017
Status Published
Journal The Journal of neuroscience : the official journal of the Society for Neuroscience
Year 2017
Date Published 11/1/2017
Volume : Pages 37 : 11271 - 11284
PubMed Reference 29038237
Abstract Engagement of integrins by the extracellular matrix initiates signaling cascades
that drive a variety of cellular functions, including neuronal migration and
axonal pathfinding in the brain. Multiple lines of evidence link the ITGB3 gene
encoding the integrin ß3 subunit with the serotonin (5-HT) system, likely via
its modulation of the 5-HT transporter (SERT). The ITGB3 coding polymorphism
Leu33Pro (rs5918, PlA2) produces hyperactive avß3 receptors that influence
whole-blood 5-HT levels and may influence the risk for autism spectrum disorder
(ASD). Using a phenome-wide scan of psychiatric diagnoses, we found significant,
male-specific associations between the Pro33 allele and attention-deficit
hyperactivity disorder and ASDs. Here, we used knock-in (KI) mice expressing an
Itgb3 variant that phenocopies the human Pro33 variant to elucidate the
consequences of constitutively enhanced avß3 signaling to the 5-HT system in the
brain. KI mice displayed deficits in multiple behaviors, including anxiety,
repetitive, and social behaviors. Anatomical studies revealed a significant
decrease in 5-HT synapses in the midbrain, accompanied by decreases in SERT
activity and reduced localization of SERTs to integrin adhesion complexes in
synapses of KI mice. Inhibition of focal adhesion kinase (FAK) rescued SERT
function in synapses of KI mice, demonstrating that constitutive active FAK
signaling downstream of the Pro32Pro33 integrin avß3 suppresses SERT activity.
Our studies identify a complex regulation of 5-HT homeostasis and behaviors by
integrin avß3, revealing an important role for integrins in modulating risk for
neuropsychiatric disorders.SIGNIFICANCE STATEMENT The integrin ß3 Leu33Pro
coding polymorphism has been associated with autism spectrum disorders (ASDs)
within a subgroup of patients with elevated blood 5-HT levels, linking integrin
ß3, 5-HT, and ASD risk. We capitalized on these interactions to demonstrate that
the Pro33 coding variation in the murine integrin ß3 recapitulates the
sex-dependent neurochemical and behavioral attributes of ASD. Using
state-of-the-art techniques, we show that presynaptic 5-HT function is altered
in these mice, and that the localization of 5-HT transporters to specific
compartments within the synapse, disrupted by the integrin ß3 Pro33 mutation, is
critical for appropriate reuptake of 5-HT. Our studies provide fundamental
insight into the genetic network regulating 5-HT neurotransmission in the CNS
that is also associated with ASD risk.




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