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Manipulation of Gene Linked to Autism Spectrum Disorder Restores Neuronal Processing of Social Behavior in Mice

Key findings

  • In mice, hemizygous knockout or haploinsufficiency of the Shank3 gene has been associated with an autism spectrum disorder (ASD)-like condition characterized by diminished social interest in others
  • In this study, SHANK3 expression was disrupted and then restored in adult mice in vivo over weeks of time while neuronal recordings and social behavior tests were conducted concurrently
  • SHANK3 disruption led to a reduction of neurons encoding the experience of other mice and an increase in neurons encoding the animal's own experience; this shift caused neurons to lose the ability to distinguish "other" from "self"
  • Restoration of SHANK3 expression in the medial prefrontal cortex improved the animals' social interest in others
  • These results advance our understanding of the brain mechanisms underlying ASD with hopes of developing therapies for patients that would help them ameliorate social behavioral deficits

Autism spectrum disorder (ASD) typically involves problems with learning how to act in different social situations. Individuals are often unable to appropriately interpret social cues and the experience and emotions of others. They may also exhibit exaggerated preoccupation with their own (or "self") emotional states.

In humans, the Shank3 gene is associated with the disruption of cortical and subcortical circuits thought to be involved in ASD. In mice, congenital hemizygous knockout of the Shank3 gene leads to diminished interest in others.

Ziv M. Williams, MD, of the Department of Neurosurgery at Massachusetts General Hospital, and colleagues observed that increasing SHANK3 protein expression by restoring homozygous Shank3 function ameliorated social behavioral deficits in genetically engineered adult mice, a finding with implications for the treatment of people with ASD. Their report appears in Nature Neuroscience.

Study Methods

The study made use of a "flip-excision" (FLEx) system, which allows manipulation of gene expression in vivo. The researchers created Shank3-deficient mice and then gradually restored SHANK3 expression as neuronal recordings and behavioral tests were made concurrently over five to eight weeks. Tamoxifen was used for brain-wide increase in SHANK3 and endoxifen was used for brain region-specific targeting.

Microelectrode arrays were implanted in each animal's medial prefrontal cortex (mPFC), an area involved in social behavior and implicated in disorders such as ASD. Neuronal responses were evaluated as mice performed various social tasks. For example, in one experiment, pairs of mice were placed in a rectangular enclosure while separated but able to view each other, and three factors were varied:

  • Social identity—familiar partner (pair-housed with the recorded mouse for at least four weeks) vs. unfamiliar partner
  • Experience—positive (receiving a food pellet) vs. negative (being in a confined narrow tube enclosure)
  • Social agency—the positive or negative experience was given to the recorded animal or its partner

Key Findings

  • Disruption of SHANK3 protein expression was associated with a reduction of mPFC neurons that encoded the other mouse's experience and an increase in neurons that encoded the animal's own experience
  • This shift was associated with a loss of ability by neurons to distinguish "other" from "self" and, therefore, inability to encode social agency
  • Such changes were not observed in wild-type mice
  • When SHANK3 expression was restored, the encoding imbalance was reversed and sociability increased
  • Restoration of SHANK3 expression specifically in the mPFC increased sociability to a similar level compared to brain-wide restoration

These results advance our understanding of the brain mechanisms underlying social deficit behaviors displayed in disorders such as ASD, implying the possibility of developing therapies for patients.

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