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Genetics and Autism: Uncovering Pathways That Matter
Studies of families affected by autism have shown that, in some cases, specific genetic mutations are shared. For about a decade now, genetically modified mouse models containing mutations similar to those present in familial cases of autism have been available (Williams 2011). In a study published last month in the Journal of Neuroscience, Yang et al. examined a mouse line containing a deletion of the gene Shank3. Shank3 encodes a protein involved in synaptic signaling with the neurotransmitter glutamate. In people, mutations in Shank3 lead to delays in child development as well as autism and Phelan-McDermid syndrome, a syndrome also characterized by autistic features (Phelan 2008). Autism often includes certain phenotypes such as abnormal social interactions, deficits in communication, and repetitive behaviors. These characteristics are all evident to some extent in Shank3 mutant mice.
Yang et al. have shown that Shank3 mutant mice have impaired long-term potentiation and impaired glutamate transmission in the hippocampus, an area of the brain that is important for formation of long-term memory. They speculate that these findings could underlie deficits in socialization observed in the mice, including recognition memories. The authors performed a battery of behavioral tests on the Shank3 mutant mice, examining everything from social interactions and memory to motor skills and communication development.
They found normal sociability behaviors in adults, while juvenile males showed lower numbers of interactions with other male mice, and active social avoidance of other mice. There was no change in this behavior in female mice, possibly mirroring the much greater prevalence of autism in human males versus females. Normal development of ultrasonic vocalizations occurred in both mutant and wild-type mouse pups, while increased repetitive self-grooming was observed in only male mice. Anxiety-like behaviors were analyzed using the elevated plus maze and with startle reflex testing, and were found to be comparable between Shank3 mutant and wild-type mice. However, motor coordination was at a distinct deficit in transgenic mice, as shown by reduced performance in the Rotarod task.
While these findings don’t match the symptoms of autism precisely, the authors note that deletion in different domains of the same gene can have different effects. While transgenic mice can model certain features of autism, genetics are almost certainly not the sole cause for autism. However, mouse models of known genetic abnormalities can help to guide researchers to pathways that are affected in autism and related disorders.
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Phelan MC (2008) Deletion 22q13.3 syndrome. Orphanet J Rare Dis 3:14.
Williams SCP. (2011). New mouse models of autism highlight need for standardized tests. Nature Medicine. 17, 1324.
Yang M, Bozdagi O, Scattoni ML, Wöhr M, Roullet FI, Katz AM, Abrams DN, Kalikhman D, Simon H, Woldeyohannes L, Zhang JY, Harris MJ, Saxena R, Silverman JL, Buxbaum JD, Crawley JN. (2012). Reduced excitatory neurotransmission and mild autism-relevant phenotypes in adolescent shank3 null mutant mice. J Neurosci. May 9;32(19):6525-41.