Altered Striatal Synaptic Function and Abnormal Behaviour inShank3Exon4-9 Deletion Mouse Model of Autism : Shank3Exon4-9 Deletion Mouse Model of Autism
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Abstract
<p class="first" id="P1">Shank3 is a multi-domain, synaptic scaffolding protein that
organizes proteins in
the postsynaptic density of excitatory synapses. Clinical studies suggest that ~0.5%
of autism spectrum disorder (ASD) cases may involve
<i>SHANK3</i> mutation/deletion. Patients with
<i>SHANK3</i> mutations exhibit deficits in cognition along with delayed/impaired
speech/language
and repetitive and obsessive/compulsive-like (OCD-like) behaviors. To examine how
mutation/deletion of
<i>SHANK3</i> might alter brain function leading to ASD, we have independently created
mice with
deletion of
<i>Shank3</i> exons 4–9, a region implicated in ASD patients. We find that homozygous
deletion
of exons 4–9 (Shank3
<sup>e4–9</sup> KO) results in loss of the two highest molecular weight isoforms of
Shank3 and a
significant reduction in other isoforms. Behaviorally, both Shank3
<sup>e4–9</sup> heterozygous (HET) and Shank3
<sup>e4–9</sup> KO mice display increased repetitive grooming, deficits in novel and
spatial object
recognition learning and memory, and abnormal ultrasonic vocalizations. Shank3
<sup>e4–9</sup> KO mice also display abnormal social interaction when paired with
one another. Analysis
of synaptosome fractions from striata of Shank3
<sup>e4–9</sup> KO mice reveals decreased Homer1b/c, GluA2, and GluA3 expression.
Both Shank3
<sup>e4–9</sup> HET and KO demonstrated a significant reduction in NMDA/AMPA ratio
at excitatory
synapses onto striatal medium spiny neurons. Furthermore, Shank3
<sup>e4–9</sup> KO mice displayed reduced hippocampal LTP despite normal baseline
synaptic transmission.
Collectively these behavioral, biochemical and physiological changes suggest Shank3
isoforms have region-specific roles in regulation of AMPAR subunit localization and
NMDAR function in the Shank3
<sup>e4–9</sup> mutant mouse model of autism.
</p>