Auditory Processing Enhancements in the TS2-Neo Mouse Model of Timothy Syndrome, a Rare Genetic Disorder Associated with Autism Spectrum Disorders

Ar, Rendall; Al, Ford; Perrino, Peter A.; R, Holly Fitch

doi:10.1007/s41252-017-0029-1

Cited by 9 publications

(27 citation statements)

References 90 publications

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“…Combined findings could reflect an interaction between intrinsic local acoustic superiorities in ASD models, and simultaneous learning deficits that degrade performance. In support of this view, TS2‐Neo mice showed no learning deficits on a radial arm maze, coupled with significant superiority over wild‐types on virtually all acoustic tasks (Rendall et al, 2017). Cntnap2 KOs showed some mild (acquisition only) learning/memory deficits on a radial arm maze, coupled with significant acoustic superiorities on several (but not all) fine‐grained acoustic tasks (EBT and PD; Truong et al, 2015).…”

Section: Discussionmentioning

confidence: 84%

“…Specifically, Cntnap2 KOs showed superiority over matched wild‐types on a fine‐grained embedded frequency (EBT) and pitch discrimination task identical to that used here (Truong et al, 2015). Similarly, TS2‐Neo mice showed acoustic superiority over matched WTs on most acoustic discrimination tasks employed (Rendall et al, 2017). Combined findings could reflect an interaction between intrinsic local acoustic superiorities in ASD models, and simultaneous learning deficits that degrade performance.…”

Section: Discussionmentioning

confidence: 96%

“…The experimental frequencies used for the pitch discrimination task deviated from the standard background frequency by as much as 75 Hz, to as little as 5 Hz. Uncued trials did not include a frequency deviant prior to the SES (Rendall et al, 2017; Truong et al, 2015).…”

Section: Methodsmentioning

confidence: 99%

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Shank3B mutant mice display pitch discrimination enhancements and learning deficits

Rendall

Perrino

Buscarello

et al. 2018

Intl J of Devlp Neuroscience

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Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by a core set of atypical behaviors in social‐communicative and repetitive‐motor domains. Individual profiles are widely heterogeneous and include language skills ranging from nonverbal to hyperlexic. The causal mechanisms underlying ASD remain poorly understood but appear to include a complex combination of polygenic and environmental risk factors. SHANK3 (SH3 and multiple ankyrin repeat domains 3) is one of a subset of well‐replicated ASD‐risk genes (i.e., genes demonstrating ASD associations in multiple studies), with haploinsufficiency of SHANK3 following deletion or de novo mutation seen in about 1% of non‐syndromic ASD. SHANK3 is a synaptic scaffolding protein enriched in the postsynaptic density of excitatory synapses. In order to more closely evaluate the contribution of SHANK3 to neurodevelopmental expression of ASD, a knockout mouse model with a mutation in the PDZ domain was developed. Initial research showed compulsive/repetitive behaviors and impaired social interactions in these mice, replicating two core ASD features. The current study was designed to further examine Shank3B heterozygous and homozygous knockout mice for behaviors that might map onto atypical language in ASD (e.g., auditory processing, and learning/memory). We report findings of repetitive and atypical aggressive social behaviors (replicating prior reports), novel evidence that Shank3B KO mice have atypical auditory processing (low‐level enhancements that might have a direct relationship with heightened pitch discrimination seen in ASD), as well as robust learning impairments.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 96%

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Shank3B mutant mice display pitch discrimination enhancements and learning deficits

Rendall

Perrino

Buscarello

et al. 2018

Intl J of Devlp Neuroscience

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“…Previous studies reported that the TS2-neo mice performed normally in spatial learning and memory, and showed repetitive/restricted behavior and impaired social interaction, dominant in a tube test [4,5]. To address behavioral phenotypes in a social domain, the feature of the IntelliCage system was utilized, that is, a group-housed condition.…”

Section: Ts2-neo Mice Show Normal Learning Flexibility and High Sociamentioning

confidence: 99%

“…G406R causes excessive Ca 2+ currents via deficits of voltage-and calcium-dependent inactivation [1,3]. A genetically modified knock-in mouse with heterogeneous TS2 (G406R) point mutation in the L-type Ca 2+ channel, TS2-neo, showed autistic traits of impaired social interaction along with restricted and repetitive/ preservative behavior [4,5].…”

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confidence: 99%

A mouse model of Timothy syndrome exhibits altered social competitive dominance and inhibitory neuron development

et al. 2020

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Multiple genetic factors related to autism spectrum disorder (ASD) have been identified, but the biological mechanisms remain obscure. Timothy syndrome (TS), associated with syndromic ASD, is caused by a gain‐of‐function mutation, G406R, in the pore‐forming subunit of L‐type Ca2+ channels, Cav1.2. In this study, a mouse model of TS, TS2‐neo, was used to enhance behavioral phenotyping and to identify developmental anomalies in inhibitory neurons. Using the IntelliCage, which enables sequential behavioral tasks without human handling and mouse isolation stress, high social competitive dominance was observed in TS2‐neo mice. Furthermore, histological analysis demonstrated inhibitory neuronal abnormalities in the neocortex, including an excess of smaller‐sized inhibitory presynaptic terminals in the somatosensory cortex of young adolescent mice and higher numbers of migrating inhibitory neurons from the medial ganglionic eminence during embryonic development. In contrast, no obvious changes in excitatory synaptic terminals were found. These novel neural abnormalities in inhibitory neurons of TS2‐neo mice may result in a disturbed excitatory/inhibitory (E/I) balance, a key feature underlying ASD.

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Communication‐related assessments in an Angelman syndrome mouse model

et al. 2020

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Introduction Angelman syndrome (AS) is a neurodevelopmental disorder characterized by motor deficits, seizures, some autistic‐like behaviors, and severe impairment of speech. A dysfunction of the maternally imprinted UBE3A gene, coupled with a functional yet silenced paternal copy, results in AS. Although studies of transgenic mouse models have revealed a great deal about neural populations and rescue timeframes for specific features of AS, these studies have largely failed to examine intermediate phenotypes that contribute to the profound communicative disabilities associated with AS. Methods Here, we use a variety of tasks, including assessments of rapid auditory processing and social communication. Expressive vocalizations were directly assessed and correlated against other core behavioral measures (motor, social, acoustic perception) to model putative influences on communication. Results AS mice displayed the characteristic phenotypes associated with Angelman syndrome (i.e., social and motor deficits), as well as marginal enhancements in rapid auditory processing ability. Our characterization of adult ultrasonic vocalizations further showed that AS mice produce fewer vocalizations and vocalized for a shorter amount of time when compared to controls. Additionally, a strong correlation between motor indices and ultrasonic vocalization output was shown, suggesting that the motor impairments in AS may contribute heavily to communication impairments. Conclusion In summary, the combination of motor deficits, social impairment, marginal rapid auditory enhancements, and altered ultrasonic vocalizations reported in a mouse model of AS clearly parallel the human symptoms of the disorder. This mouse model offers a novel route to interrogate the underlying genetic, physiologic, and behavioral influences on the under‐studied topic of impaired communication in AS.

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Auditory Processing Enhancements in the TS2-Neo Mouse Model of Timothy Syndrome, a Rare Genetic Disorder Associated with Autism Spectrum Disorders

Cited by 9 publications

References 90 publications

Shank3B mutant mice display pitch discrimination enhancements and learning deficits

Shank3B mutant mice display pitch discrimination enhancements and learning deficits

A mouse model of Timothy syndrome exhibits altered social competitive dominance and inhibitory neuron development

Communication‐related assessments in an Angelman syndrome mouse model

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