Autism-linked gene primes stress vulnerability in mice | Spectrum
Stress test: high expression of the protein HOMER1A (1, green) exaggerated the loss of SHANK3 (2, pink) from synapses in stressed mice with a mutated copy of the SHANK3 gene.
Stressful situations lead to social deficits in mice with a mutated copy of the autism-linked gene SHANK3, according to a new study. The elimination of a stress-related protein that regulates SHANK3 restores typical social functions in the animals, as the work also shows.
That connection could help explain why new environments and social interactions can be uniquely stressful for people with SHANK3 mutations, the researchers say.
SHANK3 codes for a protein that serves to support other proteins at synapses. One such protein is HOMER, which helps bind receptors for the signaling molecule glutamate.
HOMER1A, a shorter form of HOMER that is only expressed during stressful experiences and other selected circumstances, reduces SHANK3 protein levels at synapses, the new study shows. However, removing both copies of the gene coding for HOMER1A from mice lacking SHANK3 partially restores SHANK3 levels at the synapses.
“When we turn off HOMER1A in mice with SHANK3 deficiency, we allow the system to regain equilibrium,” says co-director Alena Savonenko, associate professor of pathology at Johns Hopkins University in Baltimore, Maryland.
Previous work pointed to this relationship between HOMER1A and SHANK3, but the effects of the genes on mouse behavior had not been explicitly studied, says Kimberly Huber, a neuroscience professor at Southwestern Medical Center at the University of Texas at Dallas, who was not involved in the study was working.
“We knew that HOMER1A could compete with these scaffolding and disrupt them,” she tells me. “
The results also suggest that therapies that reduce stress in people with Phelan-McDermid syndrome, an autism-related condition caused by mutations in SHANK3, might alleviate some features of the condition, Huber says.
S.avonenko and her team subjected the SHANK3 mice and the controls to a brief but stressful experience: swimming for six minutes in a small container of water. They then put the mice back in their cages for a four-hour rest period. They analyzed gene expression levels in the excitatory neurons of half of the mice and put the rest of the animals through social behavior tests.
The team found that stress induced HOMER1A expression more strongly in SHANK3 mice than in wild-type controls and attenuated SHANK3 levels at synapses more strongly. Compared to controls and unstressed SHANK3 mice, the stressed SHANK3 mice also showed a lower preference for another mouse over an inanimate object, suggesting that stress had disrupted their social motivation.
A similar pattern emerged when the team examined how much time the mice spent near an inanimate object or another mouse and how close they got to them: the stressed SHANK3 mice showed less interest in other mice than their unstressed conspecifics . However, stressed SHANK3 mice lacking both copies of HOMER1A behaved similarly to control mice. They also retained higher levels of SHANK3 protein in their synapses than stressed SHANK3 mice with intact copies of HOMER1A. The work appeared in Cell Reports in November.
“It’s really a nice genetic-environment interaction,” says Valerie Bolivar, a researcher at the Wadsworth Center of the New York State Department of Health in Albany who was not involved in the work.
However, some of the behavioral data from the study is inconclusive, says Mu Yang, an assistant professor of neurobiology at Columbia University who was not involved in the work. For example, the time the SHANK3 mice spent examining an unknown mouse was not obviously affected by stress, and the proximity measurement on which the study concluded was poorly defined, “which made it difficult to assess the robustness of the To judge the result ”. Says Yang.
Savonenko and her team plan to continue this study by examining the effects of social stress on SHANK3 mice and other mice with genetic mutations.
Cite this article: https://doi.org/10.53053/AVAH6189
