Treatment and Male-Bias in Autistic Mice

Although humans and mice are separated by 100 million years of evolution, mouse and rat models have continually proven themselves as extremely powerful research tools. Many mouse and rat genetic models can even recapitulate complex and seemingly uniquely human phenotypes. A great example are mouse models of autism spectrum disorders (ASD), which display many of the hallmark features of human ASD, including deficits in social communication and recognition, heightened anxiety, repetetive behavior, and hyperactivity. Recent work from several groups has taken advantage of ASD models to study autism and even develop potential treatments.

Male-specific autism phenotypes in mice

A striking feature of ASD is that more than 75% of diagnosed children are male. Although the reason for this sex-specific disparity is unknown, rodent models are beginningg to shed light on this aspect of the disorder. Using a contactin-associated protein-like 2 (Cntnap2) knockout mouse model for ASD, a group at the Rockefeller University analyzed the relative contributions of sex, prenatal stress, and genotype to the manifestation of ASD phenotypes¹. Interestingly, in this mouse model there is a stong male-bias in emergence of ASD phenotypes, particularly in male mice who endured prenatal stress due to maternal immune activation. In fact, the results suggest that this type of prenatal stress affects social recognition only in male mice, with no effect on female mice. These results have important implications for understanding autism in humans, as well as for studies of other neurodevelopmental disorders with male-specific vulnerabilities, such as attention deficit and hyperactivity disorder (ADHD), dyslexia, and Tourette syndrome.

Treating autism with neuromodulation

In an exciting new breakthrough, a group led by Peter Tsai at UT Southwestern identified a specific neural circuit that is implicated in ASD, and using a targeted neuromodulation approach they were able to reduce ASD deficits in mice and humans. In a Purkinje cell Tsc1 knockout mouse model of ASD, this group found specific altered structural connections with the brain region RCrusI, and could selectively generate or aleviate ASD phenotypes by inhibiting or stimulating RCrusI. Stimulation of this brain region was able to completely rescue social impairment phenotypes in this model, but did not improve some other phenotypes, such as repetitive behaviors, possibly suggesting different mechanisms for these phenotypes in this ASD model.

Cyagen Biosciences can make the custom mouse models you need for your specific research goals. We offer transgenics, knockouts, knockins, CRISPR/Cas9 and TALEN genome editing, and custom virus packaging, stem cells, and cell culture reagents. Our VectorBuilder platform allows you to order custom DNA constructs specific to your experimental needs. Choose from lentiviruses, adenovirus, AAV, shRNA expression vectors, CRISPR/Cas9 vectors, and more.

References

1. Schaafsma SM, Gagnidze K, Reyes A, Norstedt N, Månsson K, Francis K, Pfaff DW. Sex-specific gene-environment interactions underlying ASD-like behaviors. Proc Natl Acad Sci U S A. 2017 Feb 7;114(6):1383-1388.
2. Stoodley CJ, D'Mello AM, Ellegood J, Jakkamsetti V, Liu P, Nebel MB, Gibson JM, Kelly E, Meng F, Cano CA, Pascual JM, Mostofsky SH, Lerch JP, Tsai PT. Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice. Nat Neurosci. 2017 Dec;20(12):1744-1751.