Characterization of neuronal morphology in a shank3 exon 21 deletion mouse model of autism
Wednesday, Nov 13, 2013, 8:00 AM - 9:00 AM
++C.07.a. Autism: Genetic and animal models
, M. KOUSER
, P. WORLEY
, C. POWELL
Univ. of Texas At Southwestern, Dallas, TX;
Johns Hopkins Univ., Baltimore, MD
Shank3 is a multi-domain scaffolding protein in postsynaptic densities of excitatory synapses. Deletions and mutations of Shank3 have been strongly implicated in neurodevelopmental disorders such as Phelan-Mcdermid Syndrome and Autism Spectrum Disorders (ASD). Our laboratory has characterized a homozygous Shank3 Exon 21 deletion mutation mouse model that leads to loss of the major naturally occurring isoforms of Shank3 throughout the brain. These mice exhibit significant biochemical, electrophysiological, and behavioral deficits. Among the electrophysiologic deficits, we find a decrease in miniature excitatory postsynaptic currents (mEPSCs) in hippocampal area CA1 with no change in paired pulse ratio. To determine whether changes in dendritic morphology and spine density correlate with these electrophysiological deficits, we performed Golgi staining and characterized in detail dendritic morphology and dendritic spine density. Twenty pyramidal neurons from the hippocampal CA1 region per genotype (Wildtype, +/ ΔC, ΔC/ ΔC) were traced and analyzed using Neurolucida. Neurons were selected based on lack of overlap with neighboring stained neurons. Spine counting was done on the straightest possible dendritic segment at defined distances from the cell body (30, 60, 90, 120 μm). We observed no significant differences in Sholl analysis (intersections, nodes, dendritic length), neuron morphology (somatic area, total dendritic length, total nodes), and spine density among the three genotypes. These preliminary results suggest that a morphological decrease in synaptic spine density may not explain the decreased mEPSC frequency in this model, although the age between electrophysiological experiments and histological experiments differed greatly. Ongoing experiments are characterizing Shank3
mutant mice that correspond directly with the age of mice on which electrophysiology was performed.
5R01HD069560 to CMP
R01HD69560-0251 to CMP
Autism Speaks Translational Postdoctoral Fellowship to HS
Autism Speaks Pilot Award to CMP
R21HD065290 to CMP
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