A Foxp2 Mutation Implicated in Human Speech Deficits Alters Sequencing of Ultrasonic Vocalizations in Adult Male Mice

Abstract

Development of proficient spoken language skills is disrupted by mutations of the FOXP2 transcription factor. A heterozygous missense mutation in the KE family causes speech apraxia, involving difficulty producing words with complex learned sequences of syllables. Manipulations in songbirds have helped to elucidate the role of this gene in vocal learning, but findings in non-human mammals have been limited or inconclusive. Here, we performed a systematic study of ultrasonic vocalizations (USVs) of adult male mice carrying the KE family mutation. Using novel statistical tools, we found that Foxp2 heterozygous mice did not have detectable changes in USV syllable acoustic structure, but produced shorter sequences and did not shift to more complex syntax in social contexts where wildtype animals did. Heterozygous mice also displayed a shift in the position of their rudimentary laryngeal motor cortex (LMC) layer-5 neurons. Our findings indicate that although mouse USVs are mostly innate, the underlying contributions of FoxP2 to sequencing of vocalizations are conserved with humans.

MUPET—Mouse Ultrasonic Profile ExTraction: A Signal Processing Tool for Rapid and Unsupervised Analysis of Ultrasonic Vocalizations

“…We note that the large number of syllable types identified as RUs and RU-clusters by MUPET will require advanced sequence analysis approaches to analyze syntax. MSA provides an option of generating 4–15 syllable categories, enabling a simplified syntax analysis that has been used successfully to identify syntactical changes across conditions and strains (Chabout et al, 2015; Chabout et al, 2016). …”

“…USVs support essential social behaviors across development (Chabout et al, 2012; Hammerschmidt et al, 2009; Hanson and Hurley, 2012; Holy and Guo, 2005; Pomerantz et al, 1983; Sales and Pye, 1974; Sewell, 1970). Although mice are innate vocalizers (Arriaga and Jarvis, 2013; Hammerschmidt et al, 2015; Mahrt et al, 2013), the acoustic structure (e.g., mean frequency, amplitude) and contextual use of their syllable repertoires varies considerably across genetic strains (Panksepp et al, 2007; Scattoni et al, 2010; Sugimoto et al, 2011; Thornton et al, 2005; Wohr et al, 2008), behavioral and social environments (Chabout et al, 2015; Chabout et al, 2016; Hanson and Hurley, 2012; Liu et al, 2003; Yang et al, 2013), and development (Grimsley et al, 2011; Liu et al, 2003). Understanding complex vocalization structure of mice will be key to advancing vocal and social communication research.…”

No Evidence for Recent Selection at FOXP2 among Diverse Human Populations

“…FOXP2 has been shown in vitro and in vivo to affect brain development and neural plasticity in humans and mice (Chiu et al, 2014; Enard et al, 2009; Reimers-Kipping et al, 2011; Španiel et al, 2011), and its altered expression affects brain function in language-related cortical areas (Fujita-Jimbo and Momoi, 2014; Konopka et al, 2009; Pinel et al, 2012; Spiteri et al, 2007). Intriguingly, it has also been shown to affect language-like behaviors in other animals, including in birdsong and juvenile mouse vocalizations (Chabout et al, 2016; Haesler et al, 2004; Shu et al, 2005; Teramitsu et al, 2010) as well as other primates (Staes et al, 2017). To date, FOXP2 is the only known autosomal-dominant language-related gene.…”

Computational Analysis of Neonatal Mouse Ultrasonic Vocalization

“…Moreover, mouse models of such genetic variants exhibit ASD-related behaviors. Mouse call types have been assessed based on number, duration and proportions (Lai et al, 2014; Michetti, Ricceri, & Scattoni, 2012; Nishi & Hiroi, 2016), as well as call types and sequences(Burkett, Day, Penagarikano, Geschwind, & White, 2015; Chabout et al, 2016; Ey et al, 2013; Hiramoto et al, 2011; Scattoni, Gandhy, Ricceri, & Crawley, 2008; Van Segbroeck, Knoll, Levitt, & Narayanan, 2017) in genetic mouse models of ASD. Pup vocal calls clearly influence maternal care in mice (Okabe et al, 2013).…”