Behavioral characterization of Shank3 homer binding domain deletion model of autism
Wednesday, Nov 13, 2013, 10:00 AM -10:15 AM
++C.07.a. Autism: Genetic and animal models
, H. E. SPEED
, J. M. REIMERS
, C. M. DEWEY
, A. J. WIDMAN
, S. LIU
, T. C. JARAMILLO
, P. F. WORLEY
, C. M. POWELL
Neurol. and Neurotherapeutics, UTSouthwestern, Dallas, TX;
Neurosci., John Hopkins Univ. Sch. of Med., Baltimore, MD
Autism spectrum disorders (ASDs) are common, debilitating disorders affecting social interaction, communication, and repetitive behaviors. Deletion and other loss-of-function mutations of Shank3 have been strongly implicated in autism. Shank3 deletions and mutations have also been linked with Phelan-McDermid Syndrome. Shank3 is a member of shank family of post-synaptic density scaffolding proteins and is mainly found in excitatory synapses. We hypothesize that loss of major naturally occurring isoforms of Shank3 in a mouse model will lead to autism-relevant behavioral abnormalities and shed light on Shank3 synaptic function that will be important for identifying novel therapeutic strategies for at least a subset of autism.
Homozygous deletion of exon 21 of Shank3, including the C-terminal Homer binding domain, results in a loss of all major, high-molecular weight isoforms of Shank3 with the appearance of novel or increased lower molecular weight isoforms. We demonstrate that loss of these Shank3 isoforms leads to alterations in hippocampus-dependent cognitive behavior and alterations in NMDA/AMPA ratio and long-term potentiation. Additional behavioral abnormalities have been observed. These data suggest that Shank3 isoforms are required for normal synaptic transmission and plasticity in the hippocampus as well as for hippocampus-dependent cognitive function. Consistent with previous reports, potential therapeutic targets are suggested by our findings.
Autism Speaks Dennis Weatherstone Fellowship (MK)
5R01HD069560 to CMP
R01HD69560-0251 to CMP
Autism Speaks Translational Postdoctoral Fellowship to HS
Autism Speaks Pilot Award to CMP
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