Review
Ultrasonic vocalizations in Shank mouse models for autism spectrum disorders: Detailed spectrographic analyses and developmental profiles

https://doi.org/10.1016/j.neubiorev.2014.03.021Get rights and content

Highlights

  • Autism spectrum disorders (ASD) are characterized by social communication deficits.

  • Members of the SHANK gene family are promising candidate genes for ASD.

  • SHANK genes are therefore important candidates for modeling ASD in mice.

  • Shank genetic mouse models for ASD display ultrasonic communication deficits.

Abstract

Autism spectrum disorders (ASD) are a class of neurodevelopmental disorders characterized by persistent deficits in social behavior and communication across multiple contexts, together with repetitive patterns of behavior, interests, or activities. The high concordance rate between monozygotic twins supports a strong genetic component. Among the most promising candidate genes for ASD is the SHANK gene family, including SHANK1, SHANK2 (ProSAP1), and SHANK3 (ProSAP2). SHANK genes are therefore important candidates for modeling ASD in mice and various genetic models were generated within the last few years. As the diagnostic criteria for ASD are purely behaviorally defined, the validity of mouse models for ASD strongly depends on their behavioral phenotype. Behavioral phenotyping is therefore a key component of the current translational approach and requires sensitive behavioral test paradigms with high relevance to each diagnostic symptom category. While behavioral phenotyping assays for social deficits and repetitive patterns of behavior, interests, or activities are well-established, the development of sensitive behavioral test paradigms to assess communication deficits in mice is a daunting challenge. Measuring ultrasonic vocalizations (USV) appears to be a promising strategy. In the first part of the review, an overview on the different types of mouse USV and their communicative functions will be provided. The second part is devoted to studies on the emission of USV in Shank mouse models for ASD. Evidence for communication deficits was obtained in Shank1, Shank2, and Shank3 genetic mouse models for ASD, often paralleled by behavioral phenotypes relevant to social deficits seen in ASD.

Introduction

Autism spectrum disorders (ASD) are a class of neurodevelopmental disorders characterized by persistent deficits in social behavior and communication across multiple contexts, together with repetitive patterns of behavior, interests, or activities (American Psychiatric Association, 2013). Impairments in reciprocal social communication and social interaction are pervasive and sustained, with varying manifestations in verbal and nonverbal deficits. Symptom severity depends on several factors, including the individual's age, intellectual level, and language ability. Language deficits may range from a complete lack of intelligible speech and severe delays in language acquisition to reduced conversational skills due to echolalia, pronoun errors, and overly literal use of language, with stereotyped and idiosyncratic words and phrases. Even when formal aspects of language, syntax and semantics, are intact, normal back-and-forth conversation is typically impaired, particularly because of deficits in the domain of pragmatics, namely the ability to use language for communicative purposes, e.g. by taking the context of utterance into account when interpreting the meaning. As a result, comprehension of speech is often poor. Existing language thus commonly lacks social reciprocity and is used to request or label rather than to comment and converse or to share feelings and interests. The spontaneous flow of an everyday conversation with one information leading to another is missing. Deficits in verbal communication are typically paralleled by nonverbal abnormalities, such as absent, reduced, or atypical use of eye contact and body language, including total lack of facial expressions and gestures, e.g. pointing to objects to establish joint attention in order to share interest. Speech intonation often appears inappropriate. As for verbal communication, comprehension is often impaired, including deficits in understanding facial expressions and gestures. If present, verbal and nonverbal communication are typically not well integrated (American Psychiatric Association, 2013, Frith, 2003).

ASD have first been described by Kanner and Asperger about 70 years ago (Asperger, 1944, Kanner, 1943; but see also Ssucharewa, 1926) and since then tremendous progress has been made in diagnosing this class of neurodevelopmental disorders, e.g. by means of the autism diagnostic observation schedule (ADOS-2; Jones and Lord, 2013, Lord et al., 2012a, Lord et al., 2012b). Yet, the causes of ASD are still largely unknown. The high concordance rate between monozygotic twins (Folstein and Rutter, 1977, Posthuma and Polderman, 2013) supports a strong genetic component, but the specific genetic alterations underlying ASD remain elusive in the majority of cases (Abrahams and Geschwind, 2008, State, 2010). Among the most promising candidate genes for ASD is the SHANK gene family, including SHANK1, SHANK2 (ProSAP1; proline-rich synapse-associated protein-1), and SHANK3 (ProSAP2; proline-rich synapse-associated protein-2) (Grabrucker et al., 2011, Guilmatre et al., 2014, Jiang and Ehlers, 2013, Ting et al., 2012). Durand et al. (2007) first described mutations in SHANK3 in patients with ASD. Since then, genetic alterations, including point mutations and microdeletions of SHANK3, have been repeatedly reported in cases of ASD and schizophrenia patients with ASD traits (Boccuto et al., 2013, Dhar et al., 2010, Gauthier et al., 2009, Gauthier et al., 2010, Gong et al., 2012, Marshall et al., 2008, Moessner et al., 2007, Schaaf et al., 2011, Waga et al., 2011). Furthermore, SHANK3 maps to the region of the 22q13.3 Phelan-McDermid deletion syndrome (Wilson et al., 2003), a neurodevelopmental disorder characterized by language impairment and ASD features (Phelan, 2008), thus further strengthening the association between SHANK3 and social and communication behaviors. More recently, mutations in SHANK1 and SHANK2 were also found to be associated with ASD (Berkel et al., 2010, Leblond et al., 2012, Pinto et al., 2010, Sato et al., 2012).

SHANK genes encode for a family of multidomain scaffolding proteins located in the postsynaptic density of nearly all excitatory glutamatergic synapses in the mammalian brain (Grabrucker et al., 2011, Kim and Sheng, 2004, Kreienkamp, 2008, Sheng and Kim, 2000). Shank “master scaffolding proteins” (Kreienkamp, 2008, Sheng and Kim, 2000) are part of a multi-protein complex and interconnect the actin cytoskeleton of the dendritic spine with proteins of the postsynaptic membrane, including members of the NMDA and metabotropic glutamate receptor complexes (Grabrucker et al., 2011, Kim and Sheng, 2004, Kreienkamp, 2008, Sheng and Kim, 2000).

SHANK genes are therefore important candidates for modeling ASD in mice and various genetic models were generated within the last few years, with the main aims of understanding the roles of the SHANK gene family members in the etiology of ASD, discovering the neurobiological mechanisms underlying behavioral phenotypes with relevance to ASD observed in these genetic models, and, based on this, evaluating novel potential treatments for ASD. Shank1−/− null mutant mice were first generated and characterized by Hung et al. (2008). In addition, two Shank2−/− null mutant mice were established very recently (Schmeisser et al., 2012, Won et al., 2012). Finally, six Shank3−/− null mutant (Bangash et al., 2011, Bozdagi et al., 2010, Peça et al., 2011, Schmeisser et al., 2012, Wang et al., 2011) and a Shank3 overexpressing mouse line (Han et al., 2013) are available as well. A detailed overview on the various models generated was recently provided by Jiang and Ehlers (2013). Their overview includes a summary of the molecular, biochemical, synaptic, and behavioral phenotypes observed in Shank1−/−, Shank2−/−, and Shank3−/− null mutant mice.

As the diagnostic criteria for ASD are purely behaviorally defined (American Psychiatric Association, 2013), the validity of mouse models for ASD strongly depends on their behavioral phenotype. Behavioral phenotyping is therefore a key component of the current translational approach and requires sensitive behavioral test paradigms with high relevance to each diagnostic symptom category (Silverman et al., 2010). Over the last few years, a comprehensive set of mouse behavioral phenotyping assays for deficits in social behavior and communication across multiple contexts was generated, together with behavioral test paradigms to assess repetitive and stereotyped patterns of behavior (Bishop and Lahvis, 2011, Silverman et al., 2010, Wöhr and Scattoni, 2013). While behavioral phenotyping assays for social deficits and repetitive patterns of behavior, interests, or activities are well-established, the development of sensitive behavioral test paradigms to assess communication deficits in mice is a daunting challenge. Measuring ultrasonic vocalizations (USV) appears to be a promising strategy. In the first part of the review, an overview on the different types of mouse USV and their communicative functions will be provided. The second part is devoted to studies on the emission of USV in Shank mouse models for ASD. USV in other mouse models for neurodevelopmental disorders, including ASD, were recently summarized by Scattoni et al. (2009) and Michetti et al. (2012).

Section snippets

Ultrasonic vocalizations in mice: types and functions

Mice perceive and emit calls in the ultrasonic range, often referred to as USV. Typically, three distinct USV types are differentiated, mainly on the basis of the developmental stage of the mouse and social context: (I) isolation-induced USV in pups, (II) interaction-induced USV in juveniles, and (III) interaction-induced USV in adults, with emission rates and acoustic call features being strongly sex-dependent in adulthood. In adulthood, interaction-induced USV mainly occur during male–female

Ultrasonic vocalizations in mice: Shank mouse models

USV have been assessed in all Shank mouse models for ASD (Bangash et al., 2011, Bozdagi et al., 2010, Ey et al., 2013, Kouser et al., 2013, Schmeisser et al., 2012, Wang et al., 2011, Wöhr et al., 2011b, Won et al., 2012, Yang et al., 2012), with the exception of the models generated by Peça et al. (2011). In addition, USV were assessed in a Shank3 overexpressing mouse line (Han et al., 2013). For an overview on the obtained findings see Fig. 1.

Concluding remarks

The assessment of USV as a measure for communication deficits appears to be a common standard in Shank mouse models for ASD. USV have been assessed in all Shank mouse models for ASD (Bangash et al., 2011, Bozdagi et al., 2010, Ey et al., 2013, Kouser et al., 2013, Schmeisser et al., 2012, Wang et al., 2011, Wöhr et al., 2011b, Won et al., 2012, Yang et al., 2012), with the exception of the models generated by Peça et al. (2011). Overall, evidence for communication deficits was obtained in Shank1

Acknowledgements

This work was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft; DFG WO 1732/1-1) and the National Institute of Mental Health Intramural Research Program. Data were collected by MW at the National Institute of Mental Health, USA, and analyzed by MW at the Philipps-University of Marburg, Germany. I wish to thank Dr. Jacqueline N. Crawley, National Institute of Mental Health, for giving me the opportunity to conduct this research and the Howard Hughes Medical Institute

References (100)

  • Y.H. Jiang et al.

    Modeling autism by SHANK gene mutations in mice

    Neuron

    (2013)
  • R.M. Jones et al.

    Diagnosing autism in neurobiological research studies

    Behav. Brain Res.

    (2013)
  • J.C. Maggio et al.

    Experience-based vocalization of male mice to female chemosignals

    Physiol. Behav.

    (1983)
  • C.R. Marshall et al.

    Structural variation of chromosomes in autism spectrum disorder

    Am. J. Hum. Genet.

    (2008)
  • K.Z. Meyza et al.

    The BTBR T+ tf/J mouse model for autism spectrum disorders-in search of biomarkers

    Behav. Brain Res.

    (2013)
  • R. Moessner et al.

    Contribution of SHANK3 mutations to autism spectrum disorder

    Am. J. Hum. Genet.

    (2007)
  • K. Musolf et al.

    Ultrasonic courtship vocalizations in wild house mice Mus musculus

    Anim. Behav.

    (2010)
  • S. Naisbitt et al.

    Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin

    Neuron

    (1999)
  • J. Nyby

    Ultrasonic vocalizations during sex behavior of male house mice (Mus musculus): a description

    Behav. Neural Biol.

    (1983)
  • J. Nyby et al.

    Male mouse (Mus musculus) ultrasonic vocalizations to female urine: why is heterosexual experience necessary?

    Behav. Neural Biol.

    (1983)
  • S.M. Pomerantz et al.

    Female behavior is affected by male ultrasonic vocalizations in house mice

    Physiol. Behav.

    (1983)
  • F.I. Roullet et al.

    Female urine-induced male mice ultrasonic vocalizations, but not scent-marking, is modulated by social experience

    Behav. Brain Res.

    (2011)
  • G.D. Sales

    Ultrasound and aggressive behaviour in rats and other small mammals

    Anim. Behav.

    (1972)
  • D. Sato et al.

    SHANK1 deletions in males with autism spectrum disorder

    Am. J. Hum. Genet.

    (2012)
  • M.L. Scattoni et al.

    Ultrasonic vocalizations: a tool for behavioural phenotyping of mouse models of neurodevelopmental disorders

    Neurosci. Biobehav. Rev.

    (2009)
  • M.L. Scattoni et al.

    Reduced social interaction, behavioural flexibility and BDNF signalling in the BTBR T+ tf/J strain, a mouse model of autism

    Behav. Brain Res.

    (2013)
  • M.W. State

    The genetics of child psychiatric disorders: focus on autism and Tourette syndrome

    Neuron

    (2010)
  • S.W. White et al.

    Anxiety in children and adolescents with autism spectrum disorders

    Clin. Psychol. Rev.

    (2009)
  • M. Wöhr et al.

    Behavioural methods used in rodent models of autism spectrum disorders: Current standards and new developments

    Behav. Brain Res.

    (2013)
  • B.S. Abrahams et al.

    Advances in autism genetics: on the threshold of a new neurobiology

    Nat. Rev. Genet.

    (2008)
  • American Psychiatric Association

    Diagnostic and Statistical Manual of Mental Disorders

    (2013)
  • H. Asperger

    Die “Autistischen Psychopathen” im Kindesalter

    Archiv für Psychiatrie und Nervenkrankheiten

    (1944)
  • D. Benton et al.

    The influence of psychotropic drugs on the ultrasonic calling of mouse pups

    Psychopharmacology (Berl)

    (1988)
  • S. Berkel et al.

    Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation

    Nat. Genet.

    (2010)
  • S.L. Bishop et al.

    The autism diagnosis in translation: shared affect in children and mouse models of ASD

    Autism Res.

    (2011)
  • L. Boccuto et al.

    Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders

    Eur. J. Hum. Genet.

    (2013)
  • O. Bozdagi et al.

    Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication

    Mol. Autism

    (2010)
  • I. Branchi et al.

    Ultrasonic vocalizations by infant laboratory mice: a preliminary spectrographic characterization under different conditions

    Dev. Psychobiol.

    (1998)
  • D. Brunner et al.

    Anxiety, motor activation, and maternal-infant interactions in 5HT1B knockout mice

    Behav. Neurosci.

    (1999)
  • J. Chabout et al.

    Adult male mice emit context-specific ultrasonic vocalizations that are modulated by prior isolation or group rearing environment

    PLoS ONE

    (2012)
  • F. Cirulli et al.

    Behavioral and hormonal responses to stress in the newborn mouse: effects of maternal deprivation and chlordiazepoxide

    Dev. Psychobiol.

    (1994)
  • F.R. D’Amato et al.

    Pups call, mothers rush: does maternal responsiveness affect the amount of ultrasonic vocalizations in mouse pups?

    Behav. Genet.

    (2005)
  • S.U. Dhar et al.

    22q13.3 deletion syndrome: clinical and molecular analysis using array CGH

    Am. J. Med. Genet. A

    (2010)
  • C.M. Durand et al.

    Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders

    Nat. Genet.

    (2007)
  • G. Ehret et al.

    Categorial perception of mouse pup ultrasound by lactating females

    Naturwissenschaften

    (1981)
  • G. Ehret et al.

    Ultrasound recognition in house mice: key-stimulus configuration and recognition mechanisms

    J. Comp. Physiol.

    (1982)
  • E. Ey et al.

    Absence of deficits in social behaviors and ultrasonic vocalizations in later generations of mice lacking neuroligin4

    Genes Brain Behav.

    (2012)
  • E.W. Fish et al.

    Anxiolytic-like effects of escitalopram, citalopram, and R-citalopram in maternally separated mouse pups

    J. Pharmacol. Exp. Ther.

    (2004)
  • E.W. Fish et al.

    Distress vocalizations in maternally separated mouse pups: modulation via 5-HT(1A), 5-HT(1B) and GABA(A) receptors

    Psychopharmacology (Berl)

    (2000)
  • S. Folstein et al.

    Genetic influences and infantile autism

    Nature

    (1977)
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