Autism-linked mutation could blur mind’s boundary between self, others | Spectrum
Social Studies: Mice in the autism model have atypical social behavior, possibly due to the way their brain processes the feeling of “self”.
Photo by Rick Dahms
A mutation in a gene associated with autism disrupts the brain’s ability to differentiate between itself and others, according to a new study in mice. Correcting the mutation restores the ability to act socially and increases sociability, as the study also shows.
The results could help explain why autism is often associated with self-employment and difficulty interacting with others, says lead researcher Ziv Williams, associate professor of neurosurgery at Harvard University.
The results give hope that gene therapies could also alleviate social difficulties in autistic people, says Camilla Bellone, associate professor of basic neuroscience at the University of Geneva in Switzerland, who was not involved in the study. “[It’s] very exciting.”
In the new work, Williams’ team constructed mice with a mutation in a copy of a gene called SHNK3, which is disrupted in more than 1 percent of people with autism. They designed the animals so that treatment with the cancer drug tamoxifen would repair the mutated part of the gene.
The team put pairs of mice in a cage and presented them with different conditions: In one experiment, they only gave one mouse access to food; in another they put a mouse in a cramped case. Using one mouse per pair, they recorded the activity of neurons in the medial prefrontal cortex (mPFC) – a region of the brain associated with social behavior and cognition.
Self-signaling:
The team looked for differences in neural activity in response to the experiences of a recorded mouse compared to the experiences of their cage mates to determine the type of information that each cell encodes. A neuron that changes activity when a mouse is near food, but not when the mouse sees another animal near food, for example, encodes information specific to the animal’s own experience, say the explorers.
Of the mPFC neurons encoding information about the experiment, about 26 percent in wild-type mice clearly responded to the animal’s own experiences, and a similar proportion – 30 percent – showed specificity for the experiences of another mouse, found that Team.
In the SHANK3-deficient mice, however, 38 percent of the cells encoded an animal’s own experiences, while only 9 percent encoded those of other animals. The model mice were also significantly less social than their wild-type counterparts.
And while wild-type mice had subsets of neurons that responded differently to their own experiences and those of others – with little overlap – most cells in the model mice responded to both, the team found. The results appeared in Nature Neuroscience this week.
The SHANK3 mice had “a reduced ability to encode information about other animals’ experiences,” says Williams.
Williams and his colleagues then used tamoxifen to restore the SHANK3 gene in the model mice and rerun the experiments.
The proportion of neurons representing the experience of other animals gradually increased in the model mice and reached wild-type levels by the fifth week after treatment. At this point too, the sets of neurons encoding the self showed little overlap compared to others. And the shift in neural representation correlated with animals becoming more social, the team found.
Puzzle pieces:
Selective activation of SHANK3 in the mPFC rather than the whole brain produced the same results, suggesting the mPFC could be a therapeutic target, says Zhanyan Fu, group leader in synapse and circuit electrophysiology at Broad Institute in Cambridge, Massachusetts, who does was not involved in the study.
Targeted therapies are the ultimate goal, says Williams. “We do not mean to say that restoring sociability in everyone is the right thing to do. But with individuals for whom it really disturbs their life … at least [a clinical treatment] gives you a tool to help.
Williams and other researchers are looking for the best regions of the brain to target, but it’s still unclear how a mutation in SHANK3 that codes for a protein that provides structural support at synapses leads to atypical social behavior, he says.
Some social differences in SHANK3-deficient mice are due to dysfunction within the excitatory cells in the anterior cingulate cortex, a region adjacent to the mPFC, according to previous work by Fu and others. And several previous studies have shown altered function of inhibitory interneurons in the mPFC of other mouse models of autism – supporting the idea that arousal-inhibition imbalance can contribute to atypical social behavior, she says.
Future studies should further examine these mechanisms and examine whether the cells that encode information about an animal’s own experiences compared to others are receiving signals from different types of presynaptic neurons, circuitry, or brain regions, Fu says. “There are more pieces of the puzzle that we have to come up with and finally put together.”
Quote this article: https://doi.org/10.53053/SIJQ1612
