Intercourse bias emerges in new mouse mannequin with autism-linked mutation | Spectrum
Imbalanced Characteristics: Animals with mutated ADNP have motor difficulties that are more pronounced in female mice.
Photography by Rick Dahms
Mice with a mutation in an autism-related gene called ADNP show gender-specific changes in gene expression, behavior, and other traits, a new study shows. The mice can mimic some of the traits seen in humans with ADNP mutations more closely than a previously created mouse strain.
Mutations in ADNP cause a syndrome characterized by autism, intellectual disability, distinctive facial features, and low muscle tone. An earlier mouse model of this syndrome was missing a copy of the gene. To develop the new model, the same team used CRISPR to create animals with the most common ADNP mutation in humans.
Both sexes of the new model have delayed development and social difficulties – among other things, male puppies also show deposits of tau protein in the brain, which is involved in Alzheimer’s disease. Intranasal treatment of short ADNP protein fragments in the animals ameliorated many of these characteristics and gave hope for the treatment of children with ADNP mutations.
“[The new model] can help us understand how to deal with the disease in humans, ”says Albert Pinhasov, Professor of Behavioral and Molecular Psychiatry at Ariel University in the West Bank, who was not involved in the study. Since people with ADNP syndrome differ in the type of mutation they have, he notes, “It would be useful to develop additional CRISPR-based models with other mutations.”
The mice could also help researchers identify biological signatures of the syndrome, says lead researcher Illana Gozes, professor emeritus of clinical biochemistry at Tel Aviv University in Israel.
Model behavior:
The mice produce a mutated form of ADNP protein, plus half the typical amount of functional ADNP protein.
Puppies with mutated ADNP squeaked at overly simple call sequences and did not startle as easily as controls in response to noises, suggesting that their hearing development is delayed. Animals with mutated ADNP also had unusual walking patterns and other motor difficulties that were more pronounced in female mice.
Compared to controls, ADNP mice of either sex showed no preference for another mouse over an object, and they exited a metal plate they stood on more slowly when it warmed up, suggesting problems with sensory development. Male mice also groomed themselves more frequently and for longer than controls, a trait reminiscent of repetitive behaviors in humans.
Male ADNP mice had difficulty recognizing an object and exhibited abnormal brain responses after seeing a visual stimulus. By the time the males were 2 months old, their brains were covered with deposits of dew that Gozes’ team had previously found in older mice lacking a copy of ADNP and in post-mortem brain tissue of a boy with ADNP syndrome.
Treating the animals with an eight amino acid fragment of the ADNP protein called NAP reduced the buildup and alleviated other traits, the researchers found.
Treatment with NAP also corrected changes in the expression of five major genes that were often deregulated in female ADNP mice. The genes include FOXO3, which is important for the formation of dendritic spines, the neural projections that receive electrical signals from other cells.
Cells derived from people with ADNP mutations show altered expression of the same genes that could be used as biomarkers of ADNP syndrome, says Gozes. The results were published in Biological Psychiatry in September.
Translation value:
Since a mouse’s genetic background can have a significant impact on its behavior and biology, assessing the influence of specific ADNP mutations in different mouse strains can provide more clarity about the role of individual gene variants, says Nicola Grissom, assistant professor of psychology at the University of Minnesota in Minneapolis, who was not involved in the research.
The study underscores how multiple mechanisms can affect biology, says Grissom. About four times as many boys as girls are diagnosed with autism, but it’s still unclear whether the higher prevalence of autism in boys is caused by biases of determination or gender differences that affect brain development, she says. “People are investigating whether there might be differences between male and female animals in terms of the influence of genotype, and they discover that there is indeed still untapped.”
Some of the study’s results could also have translational potential. NAP has previously been tested in clinical trials for schizophrenia, mild cognitive impairment, and other brain disorders. Although these studies had mixed success, they showed that the peptide was generally safe, leading Gozes and others to speculate that it could be used to treat people with ADNP mutations.
“NAP is ready for clinical trials [for ADNP syndrome]“Says Haitham Amal, Assistant Professor of Neuromics, Cell Signaling and Translational Medicine at the Hebrew University of Jerusalem in Israel, who was not involved in the study.
The main barrier to testing NAP in clinical trials for ADNP syndrome is funding, Gozes says, but Tel Aviv University’s technology transfer arm, which holds the intellectual property rights in the peptide, is raising money to bring NAP into clinical practice to bring, and is ready to license drug development company.
Quote this article: https://doi.org/10.53053/LXGN9040
