NS‐Pten knockout mice show sex‐ and age‐specific differences in ultrasonic vocalizations

Abstract

ObjectiveThe goal of this study was to identify changes in quantitative and qualitative aspects of neonatal ultrasonic vocalizations USVs in neuron‐subset specific (NS‐Pten) knockout males and females when compared with wild‐type male and female mice.BackgroundOne signaling cascade that plays a crucial role in the development of an autistic‐like phenotype is the PI3K/Akt/mTOR pathway. Mouse models that illustrate this connection include Fmr1, Tsc1, and NS‐Pten‐deficient mice. While numerous studies have investigated ultrasonic vocalizations in Fmr1 knockout and Tsc1 heterogenous mice, none have investigated USVs in NS‐Pten knockout mice using a full spectrum recording system.MethodsWe recorded ultrasonic vocalizations from NS‐Pten wild‐type and knockout male and female mice on postnatal days 8 and 11. On these days, we measured the number and quality of calls emitted from pups when they were removed from their mothers.ResultsWe found that knockout pups emitted fewer vocalizations for both sexes (p < .05). Knockout males had calls of a shorter duration and lower peak amplitude on day 8, while showing a shorter duration, lower peak amplitude, and higher peak and fundamental frequency on day 11 (p < .001). Knockout females vocalized at a lower peak amplitude and fundamental frequency, and a higher peak frequency on day 8, while showing a shorter duration and a higher peak and fundamental frequency on day 11 (p < .001). Spectrographic analyses also revealed significant differences in call type for both genotypes and sexes (p < .05).ConclusionsThese findings demonstrate that deletion of NS‐Pten results in significant decreases in vocalizations across both sexes. Additionally, our findings indicate that the aberrant vocalizations and increased call duration seen in other mTOR models are also present in NS‐Pten knockout mice. Our study provides evidence of a connection between hyperactive mTOR signaling and neonatal ultrasonic vocalizations.

CRMP 2 mediates Sema3F‐dependent axon pruning and dendritic spine remodeling

“…The duration of the individual calls was also significantly shorter in crmp2 −/− pups in both P8 ( P = 0.011) and P12 ( P = 0.003) (Fig B). This early onset social behavior defects have been described in numerous mouse models of ASD with dendritic spine pathology , some of which also showed dendritic spine pathology later in adults . To broaden the analysis of crmp2 −/− social abnormalities also to the adult animals, we performed a three‐chamber sociability test.…”

“…Morphological changes were accompanied by altered social communication in early postnatal (P8 and P12) mutants and decreased sociability in adults (Fig ) further corroborating the role of CRMP2 in the pathogenesis of ASD. Defects in early postnatal USVs followed by dendritic spine pathology have been previously observed in several mouse models of ASD . The connection between early postnatal altered sociability and impairment of stereotyped axon pruning is much less clear.…”

Male‐specific alterations in structure of isolation call sequences of mouse pups with 16p11.2 deletion

“…Various studies have reported changes in the acoustic features like call duration, peak frequency, bandwidth, peak amplitude and call rate with age in wild-type (WT) 22 , 23 as well as in ASD models. 24 – 26 Furthermore, negative impact on mouse pup mother social communications was observed because of alteration in call sequences 27 which is analogous to human studies in which participants felt more negative states on listening to crying episodes of ASD babies. 23 , 28 Grimsley et al 23 studied development of vocalizations in mice and, using Zipf's statistic 29 and entropy analysis, 30 showed that sequences of syllables produced by pups were non-random.…”

“…Qualitative and quantitative analyses of USVs can help us in understanding various neurodevelopmental aspects like ethology, behavioural pharmacology, neurotoxicology, and behavioural neurogenetics. Various studies have reported changes in the acoustic features like call duration, peak frequency, bandwidth, peak amplitude and call rate with age in wild–type (WT) 22,23 as well as in ASD models 24‐26 . Furthermore, negative impact on mouse pup mother social communications was observed because of alteration in call sequences 27 which is analogous to human studies in which participants felt more negative states on listening to crying episodes of ASD babies 23,28 .…”

Opposite Expression Patterns of Spry3 and p75NTR in Cerebellar Vermis Suggest a Male-Specific Mechanism of Autism Pathogenesis

“…This hypothesis requires that the majority (perhaps hundreds) of individual susceptibility variants converge on sex-specific mechanisms that underpin either a female protective effect or male susceptibility effect (FPE or MSE) (27, 29). The plausibility of FPE/MSE mechanisms is supported by mouse mutants of known autism genes, which exhibit sex-specific phenotypes (77–79), the presence of X-linked regulators expressed differently in males and females (80), and the influence of sex hormones such as testosterone and estrogen on normal and abnormal brain development and function (30, 31, 81–83).…”