title: Ultrastructural analyses in the hippocampus CA1 field in Shank3-deficient mice.
abstract: BACKGROUND
  The genetics of autism spectrum disorder (hereafter referred to as "autism") are rapidly unfolding, with a significant increase in the identification of genes implicated in the disorder. Many of these genes are part of a complex landscape of genetic variants that are thought to act together to cause the behavioral phenotype associated with autism. One of the few single-locus causes of autism involves a mutation in the SH3 and multiple ankyrin repeat domains 3 (SHANK3) gene. Previous electrophysiological studies in mice with Shank3 mutations demonstrated impairment in synaptic long-term potentiation, suggesting a potential disruption at the synapse.
  
  
  METHODS
  To understand how variants in SHANK3 would lead to such impairments and manifest in the brain of patients with autism, we assessed the presence of synaptic pathology in Shank3-deficient mice at 5 weeks and 3 months of age, focusing on the stratum radiatum of the CA1 field. This study analyzed both Shank3 heterozygous and homozygous mice using an electron microscopy approach to determine whether there is a morphological correlate to the synaptic functional impairment.
  
  
  RESULTS
  As both synaptic strength and plasticity are affected in Shank3-deficient mice, we hypothesized that there would be a reduction in synapse density, postsynaptic density length, and perforated synapse density. No differences were found in most parameters assessed. However, Shank3 heterozygotes had significantly higher numbers of perforated synapses at 5 weeks compared to 3 months of age and significantly higher numbers of perforated synapses compared to 5-week-old wildtype and Shank3 homozygous mice.
  
  
  CONCLUSIONS
  Although this finding represents preliminary evidence for ultrastructural alterations, it suggests that while major structural changes seem to be compensated for in Shank3-deficient mice, more subtle morphological alterations, affecting synaptic structure, may take place in an age-dependent manner.
authors.affiliation: Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1639, New York, NY 10029 USA ; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA ; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY USA ; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA ; The Sheryl and Daniel R. Tishman Cognitive Neurophysiology Laboratory, Department of Pediatrics, Albert Einstein College of Medicine, 1225 Morris Park Avenue, Bronx, NY 10461 USA.
authors.forename: Neha
authors.initials: N
authors.lastname: Uppal
authors.affiliation: Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1639, New York, NY 10029 USA ; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA.
authors.forename: Rishi
authors.initials: R
authors.lastname: Puri
authors.affiliation: Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1639, New York, NY 10029 USA ; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Yuk
authors.affiliation: Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1639, New York, NY 10029 USA ; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA.
authors.forename: William G M
authors.initials: WG
authors.lastname: Janssen
authors.affiliation: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA ; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY USA ; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY USA.
authors.forename: Ozlem
authors.initials: O
authors.lastname: Bozdagi-Gunal
authors.affiliation: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA ; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY USA ; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY USA.
authors.forename: Hala
authors.initials: H
authors.lastname: Harony-Nicolas
authors.affiliation: Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1639, New York, NY 10029 USA ; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA ; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA.
authors.forename: Dara L
authors.initials: DL
authors.lastname: Dickstein
authors.affiliation: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA ; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY USA ; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA ; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.affiliation: Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1639, New York, NY 10029 USA ; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA ; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY USA ; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Hof
keywords: Autism; CA1; Electron microscopy; Hippocampus; Shank3; Stratum radiatum; Synapse