Altered synaptic plasticity and abnormal behaviors in Shank3 exon 4-9 mutant mouse model of autism
Tuesday, Nov 12, 2013, 11:00 AM -12:00 PM
++C.07.a. Autism: Genetic and animal models
*T. C. JARAMILLO
, H. E. SPEED, J. REIMERS, Z. XUAN, S. LIU, C. M. POWELL;
Neurol. & Neurotherapeutics, UT Southwestern Med. Ctr., Dallas, TX
Shank3 (aka Pro-SAP2) is a multi-domain, synaptic scaffolding protein that organizes glutamate receptors and scaffolding proteins in the postsynaptic density of excitatory synapses. Clinical studies suggest that ~0.5 % of autism spectrum disorder (ASD) cases may involve Shank3 mutations/deletion, suggesting a role for this gene in autism pathogenesis. Patients with Shank3 mutations exhibit deficits in cognition along with delayed speech and repetitive and obsessive/compulsive-like (OCD-like) behaviors. To examine how mutation/deletion of Shank3 might alter brain function leading to ASD, we have created mice with deletion of exons 4-9, corresponding to the ankryin repeat domain, a region implicated in ASD patients with mutations or translocation breakpoints.
Consistent with previous reports, we find that homozygous deletion of exons 4-9 (Shank3e4-9) results in a loss of only the highest molecular weight isoform of Shank3 (Shank3α). Behaviorally, Shank3e4-9 KO mice displayed increased repetitive grooming, deficits in object recognition learning and memory, abnormal ultrasonic vocalizations, normal coordination on the rotarod, and normal sociability. Biochemical analysis of synaptoneurosome fractions revealed striatum-specific deficits in GluN2B and GluR2/3 subunit expression that coincided with a reduction in NMDAR/AMPAR ratio in excitatory inputs onto striatal medium spiny neurons. There were also reduced levels of Homer1b/c and PSD-95. Furthermore, Shank3e4-9 KO mice displayed reduced hippocampal LTP, enhanced DHPG LTD and normal baseline synaptic transmission. Thus, complete loss of the highest molecular weight isoform of Shank3 in mice is sufficient to induce behavioral deficits loosely analogous to those seen in many patients with Phelan-McDermid Syndrome or ASD. Additionally, biochemical and physiological changes in Shank3-E4-9 mice suggest region-specific roles for the Shank3α isoform in regulating AMPAR and NMDAR subunit localization or expression and function. Our data suggest that replication of phenotypes across laboratories in similar genetic models will ultimately reveal the most robust behavioral phenotypes, the most relevant functional abnormalities, and ultimately the most promising therapeutic targets.
NIH Grant 5R01HD069560 to CMP
NIH Grant R01HD69560-0251 to CMP/TCJ
Autism Speaks Translational Postdoctoral Fellowship to HES
Autism Speaks Pilot Award to CMP
NIH R21HD065290 to CMP
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