Autism Research Article Review: Shank3 Mutant Mice Display Autistic-like Behaviours and Striatal Dysfunction

Previous research has shown that mutations in the Shank3 gene may play an important role in autism.  This study utilized mouse models to demonstrate that Shank3 mutations resulted in several behaviors characteristic of autism.  Although this is an animal model study it may lead to future studies that provide key insights into the possible connection between the Shank3 gene and autism.  Several tests were utilized in this study to provide correlations between the animal model and autism.

Autism Research Article Title:

Shank3 Mutant Mice Display Autistic-like Behaviours and Striatal Dysfunction by Joao Peca, Catia Feliciano, Jonathon T. Ting, et. al.

Published:

Mouse Shank3 Mutation Creates Autistic-like Behaviors in Mice
Study Focused on Shank3 Mutations Creates Autistic-like Behaviors in Mouse Model

Nature.  2011 Mar 20.  doi:10.1038/nature09965

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Study Purpose:

  • To show that Shank3 mutation in mice leads to decreased social interaction and increased repetitive and compulsive behaviors.

Background Info:

  • Shank3 has been identified as a gene possibly related to autism
  • Shank3 encodes a protein found in the postsynaptic junction
  • Proteins encoded by Shank3 form postsynaptic density (PSD) protein at glutamatergic synapses
  • Shank3B-/- (homozygous) mice showed more severe autistic-like behaviors than Shank3A and Shank3B+/- mutants
  • Shank3 protein mainly found in striatum

Study Design:

  • Grooming differences observed between the Shank3B-/- mice and the control mice.
  • Utilized Rotarod Motor Test to measure balance and coordination in mice.
  • Utilized Open Field Test to measure exploratory and anxiety-like behavior in mice (when mice are anxious they tend to prefer to stay by the walls in this test, a behavior referred to as thigmotaxis).
  • Rearing observed to gauge vertical exploration and anxiety.
  • Utilized Elevated Zero Maze to measure anxiety in the mouse models.
  • Light-Dark Emergence Test used to measure anxiety.
  • Utilized 3-Chambered Social Test to measure social novelty preference (see more info on 3-Chambered Social Test).
  • Open arena test performed to measure mouse/mouse social interactions.
  • Studied neurons and synapses from striatum to observe differences between Shank3B-/- mice and control mice.
  • Studied striatal medium spiny neurons (MSNs) in Shank3B-/- mice compared to controls.
  • Observed postsynaptic density (PSD) via electron microscopy and conducted circuitry testing in regard to neuron signaling

Study Results:

  • Grooming: Many Shank3B-/- mice engaged in grooming that resulted in skin wounds that generally became larger in size with time.  Wounds usually started on face or back of neck and spread.  Control mice did not engage in this type of self-injurious behavior.  Observations showed that these wounds were not from other animals but rather from Shank3B-/- mice spending more time grooming compared to control mice.
  • Rotarod Motor Test: No difference between Shank3B-/- and control mice.
  • Open Field Test: No difference between Shank3B-/- and control mice.
  • Rearing: Significant reduction in Shank3B-/- mice compared to controls.
  • Elevated Zero Maze: Shank3B-/- mice spent significantly less time on the open areas of the elevated zero maze than the control mice.
  • Light-Dark Emergence Test: Shank3B-/- mice spent equal amount of time as controls in light and dark portion of box but did demonstrate a delay in entering the lighted portion of the box.
  • 3-Chambered Social Test: Shank3B-/- spent more time interacting with the empty cage compared to control when only 1 cage was occupied by another mouse.  When both cages were occupied by other mice in this test the Shank3B-/- mice preferred to “avoid” both mice by staying in the middle chamber whereas the control mice showed a preference to interact with the new mouse placed in the second cage.
  • Open Arena Test: Two Shank3B-/- mice spent less time interacting with each other compared to two controls when placed in open arena.  Also observed lower rate of Shank3B -/- mouse sniffing other mouse when place in arena compared to when two control mice placed in same arena.
  • Striatum neurons and Synapses: Control mice showed more postsynaptic density (PSD) proteins compared to Shank3B-/- mice.  Possible indicator of inefficient signaling in Shank3B-/- mice.
  • Striatal Medium Spiny Neurons (MSNs): Shank3B-/- mice showed increased growth of striatal medium spiny neurons (MSNs) compared to controls.  Also, spinal MSNs found to be less dense in Shank3B-/- mice compared to control mice.
  • Postsynaptic Density (PSD) Proteins and Neuron Signaling: PSD thickness and length found to be less in Shank3B-/- mice versus controls.  Signaling inefficiency isolated to PSDs rather than a presynaptic source.

Study Strengths:

  • Mouse behavior observations were blinded
  • Tests performed to eliminate possibility of bias from nurturing by Shank3B-/- mice compared to nurturing by control mice
  • Tests performed to show lessened signaling restricted to only striatal tissue and not entire brain of Shank3B-/- mice

Study Weaknesses:

  • Study done on animal model (does not necessarily indicate the same findings would occur in humans)
  • Study performed on homozygous mice not heterozygous mice (it is thought that most individuals with autism-related Shank3 mutations have heterozygous mutations)
  • Only one observation study to determine self-injurious behavior

Comments:

  • This Shank3 study provides valuable insight into one possible cause of autism spectrum disorders.  Although these studies were conducted on mice they were able to conduct several social tests that mimicked autism-like behaviors.  Unfortunately, animal studies do not always correlate well to humans.
  • It is known that autism has many more sources than just mutations in Shank3.  Although the researchers were able to create a mouse model that mimics the social withdrawal and self-injurious behaviors often associated with autism, they used homozygous Shank3B-/- mice to achieve this.  Most cases of autism associated with Shank3B in humans are heterozygous Shank3B+/-.
  • Shank3B-/- model may be useful for future autism drug tests and for future studies focused on neuron function and social behavior.

 

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Autism News: Shank3 Mutation May Hold Clues to Autism

Autism News Update:

Mutation in Shank3 Gene May Result in Poor Brain Circuitry
Poor Synapse Function in Autism May Be Caused by Mutation in Shank3

A recent article published on May 20th, 2011 by BBC News reports key findings by scientists at MIT and Duke University.  The scientists created mice with a mutation in the Shank3 gene which encodes a protein found in neuron synapses.  This mutation led to behavior in the mice that mimicked certain autistic behaviors.  The mice in the study showed both repetitive behaviors and social difficulties.

Researchers believe that the Shank3 gene may encode a protein that plays a key role in the development of the circuitry between different parts of the brain.  Mutations in the Shank3 gene may result in poor brain connections.

If mutations in Shank3 do play a role in the development of autism then that knowledge may be key in developing targeted treatments.  However, it should be noted that only a small portion of individuals with autism likely have a mutation in the Shank3 gene.

Read the BBC News Article

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