Autism-associated insertion mutation (InsG) of shank3 exon 21 causes impaired synaptic transmission and behavioral deficits

Haley E. Speed, Mehreen Kouser, Zhong Xuan, Jeremy M. Reimers, Christine F. Ochoa, Natasha Gupta, Shunan Liu, Craig M. Powell

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

SHANK3 (also known as PROSAP2) is a postsynaptic scaffolding protein at excitatory synapses in which mutations and deletions have been implicated in patients with idiopathic autism, Phelan–McDermid (aka 22q13 microdeletion) syndrome, and other neuropsychiatric disorders. In this study, we have created a novel mouse model of human autism caused by the insertion of a single guanine nucleotide into exon 21 (Shank3<sup>G</sup>). The resulting frameshift causes a premature STOP codon and loss of major higher molecular weight Shank3 isoforms at the synapse. Shank3<sup>G/G</sup> mice exhibit deficits in hippocampus-dependent spatial learning, impaired motor coordination, altered response to novelty, and sensory processing deficits. At the cellular level, Shank3<sup>G/G</sup> mice also exhibit impaired hippocampal excitatory transmission and plasticity as well as changes in baseline NMDA receptor-mediated synaptic responses. This work identifies clear alterations in synaptic function and behavior in a novel, genetically accurate mouse model of autism mimicking an autism-associated insertion mutation. Furthermore, these findings lay the foundation for future studies aimed to validate and study region-selective and temporally selective genetic reversal studies in the Shank3<sup>G/G</sup> mouse that was engineered with such future experiments in mind.

Original languageEnglish (US)
Pages (from-to)9648-9665
Number of pages18
JournalJournal of Neuroscience
Volume35
Issue number26
DOIs
StatePublished - Jul 1 2015

Fingerprint

Insertional Mutagenesis
Autistic Disorder
Synaptic Transmission
Exons
Synapses
Guanine Nucleotides
Sequence Deletion
N-Methyl-D-Aspartate Receptors
Codon
Hippocampus
Protein Isoforms
Molecular Weight
Proteins

Keywords

  • Autism
  • Behavior
  • Phelan–McDermid syndrome
  • Postsynaptic density
  • Shank3
  • Synaptic plasticity

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Autism-associated insertion mutation (InsG) of shank3 exon 21 causes impaired synaptic transmission and behavioral deficits. / Speed, Haley E.; Kouser, Mehreen; Xuan, Zhong; Reimers, Jeremy M.; Ochoa, Christine F.; Gupta, Natasha; Liu, Shunan; Powell, Craig M.

In: Journal of Neuroscience, Vol. 35, No. 26, 01.07.2015, p. 9648-9665.

Research output: Contribution to journalArticle

Speed, HE, Kouser, M, Xuan, Z, Reimers, JM, Ochoa, CF, Gupta, N, Liu, S & Powell, CM 2015, 'Autism-associated insertion mutation (InsG) of shank3 exon 21 causes impaired synaptic transmission and behavioral deficits', Journal of Neuroscience, vol. 35, no. 26, pp. 9648-9665. https://doi.org/10.1523/JNEUROSCI.3125-14.2015
Speed, Haley E. ; Kouser, Mehreen ; Xuan, Zhong ; Reimers, Jeremy M. ; Ochoa, Christine F. ; Gupta, Natasha ; Liu, Shunan ; Powell, Craig M. / Autism-associated insertion mutation (InsG) of shank3 exon 21 causes impaired synaptic transmission and behavioral deficits. In: Journal of Neuroscience. 2015 ; Vol. 35, No. 26. pp. 9648-9665.
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