Of the core domains of impairment in autism spectrum disorders, social communication is one of the most pervasive and yet the most challenging for animal models. One potential solution, presented at IMFAR by Dr. Jacqueline Crawley (NIMH; click here for an IMFAR recap), is the study of ultrasonic vocalizations in mice. A new paper underscores the potential for this research by examining the high frequency squeaks—too high for the human ear to pick up—in a mouse model of Tuberous Sclerosis Complex (TSC), which is a genetic condition that often results in autism (approximately 40% of individuals with TSC also have autism).
Animal models of genetic syndromes that have a high incidence of autism, such as TSC, offer a unique opportunity to examine the effect of genes on specific types of animals behavior and learning. We know from previous studies that TSC mice have deficits in cognition and learning and also a higher incidence of seizures. Traditional methods for measuring the social skills of mice with a TSC mutation revealed no differences when compared with typical mice.
However, in their new paper, Dr. Lily Jan and her colleagues at UCSF and Howard Hughes Medical Institute show that TCS mice do in fact have deficits in social communication, which are revealed by measuring the high-pitched squeaks emitted by baby TSC mice. These deficits in social communication between mouse mothers and their babies occur especially when the animals are stressed. The ultrasonic squeaks are an important form of communication for the young pup who elicits these calls when separated. The calls cause mom (the mouse dam) to seek and return her pup to the safety of the nest.
Interestingly, it is the genetic status of the mouse dam and not the pup that determines whether this squeaky form of communication is typical or not. If the dams carried at least one mutated copy of the TSC gene, then their pups exhibited unusual squeaking patterns when separated, regardless of whether they themselves carried a mutated or typical (often called “wild type”) version of the gene.
Two other interesting findings in this study were reported. Male pups from dams who carried the TSC mutation were more likely to have atypical vocalizations Another curious finding was observed in examining maternal care offered by the dams. The dams who carried the mutation were also more effective in retrieving their stressed pups. These ‘super dams’ were faster to retrieve the calling babes and were also better at keeping pups in the safety of their nests.
The authors in this paper draw connections between the altered cries observed in mouse pups in this study and the atypical pitch of cries that have been observed in infants that go on to do develop autism. These comparisons and our ability to examine the biological underpinnings of the dam-pup interactions with ultrasonic vocalizations hold the potential for greater insight into communication deficits in children with autism.
5|25: Celebrating Five Years of Autism Science Day 3: Potential Reversal of Neurodevelopmental Disorders
In honor of the anniversary of Autism Speaks’ founding on Feb 25, for the next 25 days we will be sharing stories about the many significant scientific advances that have occurred during our first five years together. Our third item, Potential Reversal of Neurodevelopmental Disorders, is from Autism Speaks’ Top 10 Autism Research Events of 2007.
2007 saw the publication of several studies that documented successful treatment of disease symptoms in mouse models of three different neurodevelopmental disorders related to autism. Most significantly, two of three (Fragile X and Rett) involved reversal of the phenotype AFTER the mice had already become sick, suggesting that developmental disorders such as autism may be treatable in adolescence or adulthood.
In February 2007, researchers in Scotland found that they could reverse the debilitating defects and certain death in mice carrying the Rett Syndrome gene, well after the mice had regressed into the most severe stages of disease. In July, researchers at Massachusetts Institute of Technology used a mouse model of Fragile X syndrome to show that it was possible to reverse Fragile X and autistic symptoms after birth. Although the specific treatment approaches may not be directly applicable to an eventual autism treatment, the successful and entirely unexpected “rescue” of adult animals taught the world that so-called “developmental” disorders, those that begin in infancy, apparently still have a potential to be reversed later in life.
Given the behavioral overlap of these disorders with autism, even if the underlying disease-causing biological mechanisms are different, these results provided hope to scientists and families alike that we can (and will!) do the same for autism.
Update since this story was first run: These experiments changed the mindset of scientists worldwide, serving as a proof-of-principle for the many researchers now searching for pharmacological methods to treat these and other animal models of neurodevelopmental disorders. In a 2009 publication from the Proceedings of the National Academy of Science, researchers from MIT reported that a pharmacological treatment of the Rett syndrome mouse extended the lifespan of the animals and partially rescued a variety of symptoms, including irregular heart and breathing patterns. Studies such as these are paving the way for future human clinical trials.