Dataset Information

A Mutation Associated with Stuttering Alters Mouse Pup Ultrasonic Vocalizations.

ABSTRACT: A promising approach to understanding the mechanistic basis of speech is to study disorders that affect speech without compromising other cognitive or motor functions. Stuttering, also known as stammering, has been linked to mutations in the lysosomal enzyme-targeting pathway, but how this remarkably specific speech deficit arises from mutations in a family of general "cellular housekeeping" genes is unknown. To address this question, we asked whether a missense mutation associated with human stuttering causes vocal or other abnormalities in mice. We compared vocalizations from mice engineered to carry a mutation in the Gnptab (N-acetylglucosamine-1-phosphotransferase subunits alpha/beta) gene with wild-type littermates. We found significant differences in the vocalizations of pups with the human Gnptab stuttering mutation compared to littermate controls. Specifically, we found that mice with the mutation emitted fewer vocalizations per unit time and had longer pauses between vocalizations and that the entropy of the temporal sequence was significantly reduced. Furthermore, Gnptab missense mice were similar to wild-type mice on an extensive battery of non-vocal behaviors. We then used the same language-agnostic metrics for auditory signal analysis of human speech. We analyzed speech from people who stutter with mutations in this pathway and compared it to control speech and found abnormalities similar to those found in the mouse vocalizations. These data show that mutations in the lysosomal enzyme-targeting pathway produce highly specific effects in mouse pup vocalizations and establish the mouse as an attractive model for studying this disorder.

SUBMITTER: Barnes TD

PROVIDER: S-EPMC5063665 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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A Mutation Associated with Stuttering Alters Mouse Pup Ultrasonic Vocalizations.

Barnes Terra D TD Wozniak David F DF Gutierrez Joanne J Han Tae-Un TU Drayna Dennis D Holy Timothy E TE

Current biology : CB 20160413

A promising approach to understanding the mechanistic basis of speech is to study disorders that affect speech without compromising other cognitive or motor functions. Stuttering, also known as stammering, has been linked to mutations in the lysosomal enzyme-targeting pathway, but how this remarkably specific speech deficit arises from mutations in a family of general "cellular housekeeping" genes is unknown. To address this question, we asked whether a missense mutation associated with human st ...[more]

PMID: 27151663

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Project description:Animal models can help elucidate the mechanisms through which early-life stress (ELS) has pathophysiological effects on the developing brain. One model that has been developed for rodents consists of limiting the amount of bedding and nesting material during the first postnatal weeks of pup life. This ELS environment has been shown to induce "abusive" behaviors by rat dams towards pups, while mouse dams have been hypothesized to display "fragmented care". Here, as part of an ongoing study of gene-environment interactions that impact brain development, we analyzed long observation periods of wild-type C57Bl/6J dams caring for wild-type and Met heterozygous pups. Met encodes for the MET receptor tyrosine kinase, which is involved in cortical and hippocampal synaptogenesis. Dams with limited resources from postnatal day (P)2 to P9 preserved regular long on-nest periods, and instead increased the number of discrete dam-pup interactions during regular off-nest periods. Immediately after dams entered the nest during off-nest periods in this ELS environment, pups responded to these qualitatively different interactions with an increased number of ultrasonic vocalizations (USV) and audible vocalizations (AV), communication signals that have been associated with aversive and painful stimuli. After returning to control conditions, nest entry behaviors normalized, and dams did not show altered anxiety-like or contextual fear learning behaviors after pup weaning. Furthermore, female mice that had undergone ELS as pups did not show atypical nest entry behaviors in control conditions in adulthood, suggesting that these specific maternal behaviors are not learned during the ELS period. The results suggest that atypical responses of both mother and pups during exposure to this ELS environment likely contribute to long-term negative outcomes in mice, and that these responses more closely resemble the effects of limited bedding on rat dams and pups than was previously suggested. Discerning how different early-life stressors mediate changes in maternal-pup interactions can help elucidate the mechanisms of ELS on brain development and behavior.

Dataset Information

A Mutation Associated with Stuttering Alters Mouse Pup Ultrasonic Vocalizations.

Publications

A Mutation Associated with Stuttering Alters Mouse Pup Ultrasonic Vocalizations.

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