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

Scattoni, María Luisa; Crawley, Jacqueline N.; Ricceri, Laura

doi:10.1016/j.neubiorev.2008.08.003

Cited by 421 publications

(407 citation statements)

References 87 publications

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“…This attenuation in vocalization is reminiscent of reduced communication in ASD. Fewer calls have been reported for pups lacking oxytocin, oxytocin receptor, neuroligin-4, and FoxP2 (11,19). On the other hand, pups of the MALTT mouse, the chromosome 15q11-13 duplication model, and the inbred strain BTBR T+tf/J display increased levels of vocalization (20).…”

Section: Discussionmentioning

confidence: 99%

Mouse model of Timothy syndrome recapitulates triad of autistic traits

Bader

Faizi²,

Kim

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

185

203

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Autism and autism spectrum disorder (ASD) typically arise from a mixture of environmental influences and multiple genetic alterations. In some rare cases, such as Timothy syndrome (TS), a specific mutation in a single gene can be sufficient to generate autism or ASD in most patients, potentially offering insights into the etiology of autism in general. Both variants of TS (the milder TS1 and the more severe TS2) arise from missense mutations in alternatively spliced exons that cause the same G406R replacement in the Ca V 1.2 L-type calcium channel. We generated a TS2-like mouse but found that heterozygous (and homozygous) animals were not viable. However, heterozygous TS2 mice that were allowed to keep an inverted neomycin cassette (TS2-neo) survived through adulthood. We attribute the survival to lowering of expression of the G406R L-type channel via transcriptional interference, blunting deleterious effects of mutant L-type channel overactivity, and addressed potential effects of altered gene dosage by studying Ca V 1.2 knockout heterozygotes. Here we present a thorough behavioral phenotyping of the TS2-neo mouse, capitalizing on this unique opportunity to use the TS mutation to model ASD in mice. Along with normal general health, activity, and anxiety level, TS2-neo mice showed markedly restricted, repetitive, and perseverative behavior, altered social behavior, altered ultrasonic vocalization, and enhanced tonecued and contextual memory following fear conditioning. Our results suggest that when TS mutant channels are expressed at levels low enough to avoid fatality, they are sufficient to cause multiple, distinct behavioral abnormalities, in line with the core aspects of ASD.utism and autism spectrum disorder (ASD) are characterized by the concomitant occurrence of impaired social interaction; restricted, perseverative, and stereotypical behavior; and abnormal communication skills (1). However, the etiology remains largely unknown, in large part because most cases of ASD arise from a mixture of multiple environmental and multiple genetic influences (2), making it difficult to forge causal links to behavior. In the face of such complexity, insights might be gleaned from simple forms of ASD, generated by single, highly penetrant mutations. Timothy syndrome (TS), is a rare disorder strongly associated with autism or ASD (penetrance w75%; P = 1.2 × 10 −8 ). Other symptoms of TS include long QT syndrome, webbed fingers and toes, dysmorphic facial features, and immunodeficiency (3). Importantly, Splawski et al. (3) traced the disease to a single nucleotide mutation in the gene encoding the pore-forming subunit of an L-type calcium channel (Ca V 1.2). This sporadic glycine-to-arginine mutation is located at position 406 in exon 8A [Splawski's terminology (3), VNDAV-coding exon, low (w20%) expression in brain and heart]. If a Gly-toArg mutation occurs in the more highly (w80%) expressed (4) alternative exon 8 (MQDAM-coding exon, 59 of exon 8A) it causes a more severe variant of TS (TS2). In heterologous expression ...

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Section: Discussionmentioning

confidence: 99%

Mouse model of Timothy syndrome recapitulates triad of autistic traits

Bader

Faizi²,

Kim

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

185

203

View full text Add to dashboard Cite

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“…Ultrasonic vocalizations (USVs) produced by mouse pups when they are isolated from their mother have been suggested to be a means by which the pups seek parental care. Notably, this form of communication is disrupted in various mouse models of autism (26)(27)(28). To determine if there is a defect in USV production in AS mice we recorded and quantified USVs emitted by wild-type and AS littermates when isolated from their homecage for 4 min.…”

Section: As Mice Display An Altered Developmental Time Course Of Ultrmentioning

confidence: 99%

Seizure-like activity in a juvenile Angelman syndrome mouse model is attenuated by reducing Arc expression

Mandel‐Brehm

Salogiannis

Dhamne

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Angelman syndrome (AS) is a neurodevelopmental disorder arising from loss-of-function mutations in the maternally inherited copy of the UBE3A gene, and is characterized by an absence of speech, excessive laughter, cognitive delay, motor deficits, and seizures. Despite the fact that the symptoms of AS occur in early childhood, behavioral characterization of AS mouse models has focused primarily on adult phenotypes. In this report we describe juvenile behaviors in AS mice that are strain-independent and clinically relevant. We find that young AS mice, compared with their wild-type littermates, produce an increased number of ultrasonic vocalizations. In addition, young AS mice have defects in motor coordination, as well as abnormal brain activity that results in an enhanced seizure-like response to an audiogenic challenge. The enhanced seizure-like activity, but not the increased ultrasonic vocalizations or motor deficits, is rescued in juvenile AS mice by genetically reducing the expression level of the activity-regulated cytoskeleton-associated protein, Arc. These findings suggest that therapeutic interventions that reduce the level of Arc expression have the potential to reverse the seizures associated with AS. In addition, the identification of aberrant behaviors in young AS mice may provide clues regarding the neural circuit defects that occur in AS and ultimately allow new approaches for treating this disorder.Angelman syndrome | ARC | EPHEXIN5 | ultrasonic vocalizations | EEG

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“…As an anxiety-related behavior in neonatal mice, we recorded maternal separation-induced USVs 40,44 and examined the effects of minocycline on the USVs. In WT mice treated with vehicle, USVs emerged soon after birth and peaked at PD 7.…”

Section: Patdp!mentioning

confidence: 99%

Altered Microglia in the Amygdala Are Involved in Anxiety-related Behaviors of a Copy Number Variation Mouse Model of Autism

et al. 2015

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Background and Purpose: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a strong genetic basis. Although anxiety is a common major psychiatric condition in ASD, the underlying mechanisms of the anxiety are poorly understood. In individuals with ASD, evidence indicates a structural abnormality in the amygdala, a key component involved in anxiety and social behavior. Microglia, which are central nervous system-resident immune cells implicated in neurodevelopmental processes, are also reportedly altered in ASD. In the present study, we examined the involvement of microglia in the anxiety-related behaviors of ASD model mouse. Methods:Mice that have a 6.3-Mb paternal duplication (patDp! +) corresponding to human chromosome 15q11-q13 were used as an ASD model. Iba1, a microglial activation marker, was examined in the amygdala using immunofluorescence. Effects of perinatal treatment with minocycline, a microglial modulator, on anxiety-related behaviors were examined in neonatal and adolescent patDp! + mice.

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

Cited by 421 publications

References 87 publications

Mouse model of Timothy syndrome recapitulates triad of autistic traits

Mouse model of Timothy syndrome recapitulates triad of autistic traits

Seizure-like activity in a juvenile Angelman syndrome mouse model is attenuated by reducing Arc expression

Altered Microglia in the Amygdala Are Involved in Anxiety-related Behaviors of a Copy Number Variation Mouse Model of Autism

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