From UBE3A to Angelman syndrome: a substrate perspective

Angelman syndrome (AS) is a debilitating neurodevelopmental disorder that is characterized by motor dysfunction, intellectual disability, speech impairment, seizures and common features of autism spectrum disorders (ASDs). Some of these AS related phenotypes can be seen in other neurodevelopmental disorders (Williams, 2011;Tan et al., 2014). AS patients commonly carry mutations that render the maternally inherited UBE3A gene nonfunctional. Duplication of the chromosomal region containing the UBE3A gene is associated with ASDs. Although the causative role for UBE3A gene mutations in AS is well established, a long-standing challenge in AS research has been to identify neural substrates of UBE3A, an E3 ubiquitin ligase. A prevailing hypothesis is that changes in UBE3A protein levels would alter the levels of a collection of protein substrates, giving rise to the unique phenotypic aspects of AS and possibly UBE3A associated ASDs. Interestingly, proteins altered in AS are linked to additional ASDs that are not previously associated with changes in UBE3A, indicating a possible molecular overlap underlying the broad-spectrum phenotypes of these neurogenetic disorders. This idea raises the possibility that there may exist a one-size-fits-all approach to the treatment of neurogenetic disorders with phenotypes overlapping AS. Furthermore, while a comprehensive list of UBE3A substrates and downstream affected pathways should be developed, this is only part of the story. The timing of when UBE3A protein functions, through either changes in UBE3A or possibly substrate expression patterns, appears to be critical for AS phenotype development. These data call for further investigation of UBE3A substrates and their timing of action relevant to AS phenotypes

Early-Life Social Isolation Influences Mouse Ultrasonic Vocalizations during Male-Male Social Encounters

<div><p>Early-life social isolation has profound effects on adult social competence. This is often expressed as increased aggression or inappropriate displays of courtship-related behaviors. The social incompetence exhibited by isolated animals could be in part due to an altered ability to participate in communicatory exchanges. House mice (<i>Mus musculus</i>) present an excellent model for exploring this idea, because social isolation has a well-established influence on their social behavior, and mice engage in communication via multiple sensory modalities. Here, we tested the prediction that social isolation during early life would influence ultrasonic vocalizations (USVs) emitted by adult male mice during same-sex social encounters. Starting at three weeks of age, male mice were housed individually or in social groups of four males for five weeks, after which they were placed in one of three types of paired social encounters. Pair types consisted of: two individually housed males, two socially housed males, or an individually housed and a socially housed male (“mixed” pairs). Vocal behavior (USVs) and non-vocal behaviors were recorded from these 15-minute social interactions. Pairs of mice consisting of at least one individually housed male emitted more and longer USVs, with a greater proportional use of USVs containing frequency jumps and 50-kHz components. Individually housed males in the mixed social pairs exhibited increased levels of mounting behavior towards the socially housed males. Mounting in these pairs was positively correlated with increased number and duration of USVs as well as increased proportional use of spectrally more complex USVs. These findings demonstrate that USVs are part of the suite of social behaviors influenced by early-life social isolation, and suggest that altered vocal communication following isolation reflects reduced social competence.</p></div

Mean durations of specific USV types emitted by pairs of male mice with different social histories.

<p>(a) Mean durations of 70-kHz plain, 70-kHz jump, 50-kHz plain, and 50-kHz jump ultrasonic vocalizations (USVs) emitted by IND-IND and IND-SOC pairs of male mice. SOC-SOC pairs were not included in this two-way analysis, because few SOC-SOC pairs emitted all four USV types. Bar heights represent means ± S.E.M; bars with different letters indicate statistical differences among different USV types (Bonferroni post-hoc tests, p < 0.05). There was also a main effect of pair type: IND-SOC pairs emitted longer duration USVs than IND-IND pairs. (b) Mean duration of 70-kHz plain USVs emitted by pairs of male mice with different social histories. Bar heights represent means ± S.E.M; bars with different letters are statistically different (Bonferroni post-hoc tests, p < 0.05). IND = individually housed male; SOC = socially housed male. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0169705#sec002" target="_blank">methods</a> for additional details regarding housing history.</p

Social history influenced the total durations of social investigation behaviors performed by pairs of male mice.

<p>(a) Nose-to-nose investigation exhibited by pairs of male mice with different social histories. (b) Anogenital investigation exhibited by pairs of male mice with different social histories. Bar heights represent means ± S.E.M; bars with different letters are statistically different (Kruskal-Wallis tests with Bonferroni post-hoc tests, p < 0.05). IND = individually housed male; SOC = socially housed male. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0169705#sec002" target="_blank">methods</a> for additional details regarding housing history.</p

Spectrograms of representative ultrasonic vocalizations (USVs) produced by male mice during same-sex social encounters.

<p>USVs were classified based on frequency (50-kHz vs. 70-kHz) and the presence of frequency jumps, yielding four USV types: “70-kHz plain”, “70-kHz jump”, “50-kHz plain”, and “50-kHz jump”. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0169705#sec002" target="_blank">methods</a> for more details regarding ultrasonic vocalization classification.</p

Social history influences the proportional use of different ultrasonic vocalization (USV) types emitted by pairs of male mice.

<p>(a) Proportional use of 70-kHz plain USVs. (b) Proportional use of 70-kHz jump USVs. (c) Proportional use of 50-kHz plain USVs. (d) Proportional use of 50-kHz jump USVs. Bar heights represent means ± S.E.M; bars with different letters are statistically different (Kruskal-Wallis tests with Bonferroni post-hoc tests, p < 0.05). IND = individually housed male; SOC = socially housed male. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0169705#sec002" target="_blank">methods</a> for additional details regarding housing history and USV types.</p

Social history influences the total number and duration of ultrasonic vocalizations (USVs) emitted by male mice.

<p>(a) Total number of USVs emitted by pairs of male mice with different social histories. (b) Mean duration of USVs emitted by pairs of male mice with different social housing histories. Bar heights represent means ± S.E.M; bars with different letters are statistically different (Kruskal-Wallis tests with Bonferroni post-hoc tests, p < 0.05). IND = individually housed male; SOC = socially housed male. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0169705#sec002" target="_blank">methods</a> for additional details regarding housing history.</p

Mounting behavior is correlated with several aspects of ultrasonic vocalizations emitted by pairs of male mice with different social histories.

<p>(a) Mounting versus total ultrasonic vocalizations (USVs). (b) Mounting versus USV duration. (c) Mounting versus proportional use of 70-kHz plain USVs. (d) Mounting versus proportional use of 50-kHz jump USVs. Black circles: IND-IND pairs; white circles: IND-SOC pairs; gray circles: SOC-SOC pairs. IND = individually housed male; SOC = socially housed male. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0169705#sec002" target="_blank">methods</a> for additional details regarding housing history.</p

Number of mounting occurrences performed by pairs of male mice with different social histories.

<p>For IND-SOC pairs, IND males mounted SOC males. Bar heights represent means ± S.E.M; bars with different letters are statistically different (Kruskal-Wallis test with Bonferroni post-hoc tests, p < 0.05). IND = individually housed male; SOC = socially housed male. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0169705#sec002" target="_blank">methods</a> for additional details regarding housing history.</p