Altered ultrasonic vocalizations in a tuberous sclerosis mouse model of autism.
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.
Young
David M
DM
Department of Physiology, Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA.
Schenk
A Katrin
AK
Yang
Shi-Bing
SB
Jan
Yuh Nung
YN
Jan
Lily Yeh
LY
D000818:Animals; D001321:Autistic Disorder / Q000503:physiopathology* / Q000523:psychology; D004195:Disease Models, Animal; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008425:Maternal Behavior; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012727:Sex Characteristics; D012919:Social Behavior; D013018:Sound Spectrography; D014402:Tuberous Sclerosis / Q000235:genetics / Q000503:physiopathology* / Q000523:psychology; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics; D014465:Ultrasonics; D014828:Vocalization, Animal / Q000502:physiology*
C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins