Altered ultrasonic vocalizations in a tuberous sclerosis mouse model of autism

Abstract

Tuberous sclerosis (TSC) is an autosomally dominant neurocutaneous disease notable for its high comorbidity with autism in human patients. Studies of murine models of tuberous sclerosis have found defects in cognition and learning, but thus far have not uncovered deficits in social behaviors relevant to autism. To explore social communication and interaction in TSC2 heterozygous mice, we recorded ultrasonic vocalizations (USV) and found that although both wild-type (WT) and heterozygous pups born to WT dams showed similar call rates and patterns, baseline vocalization rates were elevated in pups born to heterozygous dams. Further analysis revealed several robust features of maternal potentiation in all but WT pups born to heterozygous dams. This lack of potentiation is suggestive of defects in mother-pup social interaction during or before the reunion period between WT pups and heterozygous dams. Intriguingly, male pups of both genotypes born to heterozygous dams showed particularly heightened call rates and burst patterns. Because our maternal retrieval experiments revealed that TSC2 +/− dams exhibited improved defensive reactions against intruders and highly efficient pup retrieval performance, the alterations in their pups' USVs and maternal potentiation do not appear to result from poor maternal care. These findings suggest that a pup's interaction with its mother strongly influences the pup's vocal communication, revealing an intriguing dependence of this social behavior on TSC2 gene dosage of both parties involved. Our study of this murine model thus uncovers social abnormalities that arise from TSC haploinsufficiency and are suggestive of autism.USV | TSC | mTOR | maternal care | social communication

Epilepsy and Autism

“…It is entirely possible that whatever sets this group apart is also responsible for the "nonresponse" to antiepileptic intervention, and that the link between autism and epilepsy lies within a common pathophysiologic substrate responsible for the child's vulnerability to both conditions. Mouse models of TSC show behavioral changes paralleling human disease phenotypes, including seizures, deficits in learning and memory, and ALB (Ehninger et al 2008;Meikle et al 2008;Young et al 2010;Tsai et al 2012).…”

Evaluation of Pax6 mutant rat as a model for autism

“…Low levels of this type of infant vocalization may be relevant to the statements by some parents that their autistic children seldom cried and were easy to raise [58]. In literature, several autism models with mutations in Foxp2, Nlgn4, and Tsc2 exhibit reduced USV [59][60][61]. Here we detected unusual properties of vocalizations in only female rSey 2 /+ rat pups.…”

Novel Animal Models of Pediatric Epilepsy

“…Mice homozygous for the loss of Tsc1 or Tsc2 die in mid-embryogenesis of apparent cardiac malformations and liver hypoplasia [103][104][105], whereas heterozygous animals are viable and develop renal and liver tumors. These mice do not exhibit a clear phenotype of TSC central nervous system involvement, except that altered ultrasonic vocalizations that suggest social abnormalities have been reported in Tsc2+/− mice [106]. In the central nervous system of Tsc2+/− and Tsc1+/− mice, the number of astrocytes is increased, which suggests that hamartin and tuberin are important astrocyte growth regulators [107].…”