Behavioral Abnormalities and Circuit Defects in the Basal Ganglia of a Mouse Model of 16p11.2 Deletion Syndrome

Portmann, Thomas; Yang, Mu; Mao, Rong; Panagiotakos, Georgia; Ellegood, Jacob; Dölen, Gül; Bader, Patrick L.; Grueter, Brad A.; Goold, Carleton P.; Er, Fisher; Clifford, Katherine M; Rengarajan, Pavitra; Kalikhman, David; Loureiro, Darren; Saw, Nay L.; Zhengqui, Zhou; Miller, Michael A.; Lerch, Jason P.; Henkelman, R. Mark; Shamloo, Mehrdad; Malenka, Robert C.; Crawley, Jacqueline N.; Dolmetsch, Ricardo

doi:10.1016/j.celrep.2014.03.036

Cited by 219 publications

(353 citation statements)

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“…There was also an apparent dosage affect, where the 16p11.2 (df/+) was larger than the WT that was larger than the 16p11.2 (dp/+). The 16p11.2 deletion was recently re-examined on a different background that was independently generated [28]. Portmann et al [28] examined the 16p11.2 deletion (+/−) model at a different age (postnatal day 7) than Horev et al [54]; however, similar to the study by Horev et al [54], several relative volume increases were seen in midline structures throughout the brain [28].…”

Section: Recent Investigations (2010-14)mentioning

confidence: 57%

“…Repetitive behaviors in mice include unusually long bouts of self-grooming, digging, and burying foreign objects such as marbles. High levels of stereotyped or repetitive behaviors have been reported in mice with mutations in genes including Shank3 [15], 16p11.2 deletion [28,54], Cntnap2 [17], and Ephrin-A [27] in the inbred strains of BTBR [6,[55][56][57], C58/J [58], and in deer mice [59].…”

Section: Discoveries Of Autism-relevant Behaviors In Mouse Modelsmentioning

confidence: 99%

“…Although anxiety is a common feature of FXS, Fmr1 KO mice display low anxiety-like behaviors [69]. Low scores on learning and memory tasks such as water maze spatial navigation, fear-conditioned freezing, novel object recognition, and touchscreen visual discrimination were seen in mice with mutations in genes including Nf1, En2, 16p11.2 deletion, and Plaur with decreased gamma-aminobutryic acid-ergic cortical interneurons [20,28,[70][71][72]. Further investigations of phenotypes in mice that have face validity and neuroanatomical construct validity to both diagnostic and associated symptoms of autism may prove particularly revealing.…”

Section: Discoveries Of Autism-relevant Behaviors In Mouse Modelsmentioning

confidence: 99%

“…Employing our 3-chambered social approach task, a simple yes-or-no assay for sociability [13], absence of sociability was reported in mice with mutations in genes including Shank3 [15,16], Cntnap2 [17], Pten [18], Tsc1 [19], En2 [20], Gabrb3 [21], Ube3a triplication [22], and oxytocin receptor knockouts [23]. Normal 3-chambered social approach appeared in mice with mutations in genes including oxytocin [24], Shank1 [25], Nlgn2 [26], Ephrin-A [27] and 16p11.2 deletion [28] Variable findings on social approach across laboratories and in mouse lines generated on different genetic backgrounds have been reported for mutations including Fmr1 [29,30], Nlgn3 [31][32][33][34], and Nlgn4 [35,36]. Social deficits on the 3-chambered sociability have been wellreplicated in 2 inbred strains of mice, BTBR [10,12,[37][38][39][40][41][42][43][44] and Balb/cJ [45,46].…”

Section: Discoveries Of Autism-relevant Behaviors In Mouse Modelsmentioning

confidence: 99%

“…The 16p11.2 deletion was recently re-examined on a different background that was independently generated [28]. Portmann et al [28] examined the 16p11.2 deletion (+/−) model at a different age (postnatal day 7) than Horev et al [54]; however, similar to the study by Horev et al [54], several relative volume increases were seen in midline structures throughout the brain [28]. Comparisons between the voxel-wise maps between both 16p11.2 deletion studies showed remarkable overlap considering the different generation of the mice, as well as different backgrounds, ages, and sex.…”

Section: Recent Investigations (2010-14)mentioning

confidence: 99%

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Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism

2015

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In order to understand the consequences of the mutation on behavioral and biological phenotypes relevant to autism, mutations in many of the risk genes for autism spectrum disorder have been experimentally generated in mice. Here, we summarize behavioral outcomes and neuroanatomical abnormalities, with a focus on highresolution magnetic resonance imaging of postmortem mouse brains. Results are described from multiple mouse models of autism spectrum disorder and comorbid syndromes, including the 15q11-13, 16p11.2, 22q11.2, Cntnap2, Engrailed2, Fragile X, Integrinβ3, MET, Neurexin1a, Neuroligin3, Reelin, Rett, Shank3, Slc6a4, tuberous sclerosis, and Williams syndrome models, and inbred strains with strong autism-relevant behavioral phenotypes, including BTBR and BALB. Concomitant behavioral and neuroanatomical abnormalities can strengthen the interpretation of results from a mouse model, and may elevate the usefulness of the model system for therapeutic discovery.

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Section: Recent Investigations (2010-14)mentioning

confidence: 57%

Section: Discoveries Of Autism-relevant Behaviors In Mouse Modelsmentioning

confidence: 99%

Section: Discoveries Of Autism-relevant Behaviors In Mouse Modelsmentioning

confidence: 99%

Section: Discoveries Of Autism-relevant Behaviors In Mouse Modelsmentioning

confidence: 99%

Section: Recent Investigations (2010-14)mentioning

confidence: 99%

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Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism

2015

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The Emerging Clinical Neuroscience of Autism Spectrum Disorder

et al. 2018

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The advent of next-generation sequencing technology, advanced imaging techniques, and cutting-edge molecular techniques for modeling ASD has allowed researchers to define ASD risk-related biological pathways and circuits that may, for the first time, unify the effects of disparate risk factors into common neurobiological mechanisms. The path from these mechanisms to biological treatments that improve the lives of individuals with autism remains unclear, but the cumulative output of multiple lines of research suggests that subtyping by genetic risk factors may be a particularly tractable way to capitalize on individual differences amenable to specific treatments.

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16p11.2 Deletion Syndrome Mice Display Sensory and Ultrasonic Vocalization Deficits During Social Interactions

et al. 2015

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Recurrent deletions and duplications at chromosomal region 16p11.2 are variably associated with speech delay, autism spectrum disorder, developmental delay, schizophrenia, and cognitive impairments. Social communication deficits are a primary diagnostic symptom of autism. Here we investigated ultrasonic vocalizations (USVs) in young adult male 16p11.2 deletion mice during a novel three-phase male–female social interaction test that detects vocalizations emitted by a male in the presence of an estrous female, how the male changes its calling when the female is suddenly absent, and the extent to which calls resume when the female returns. Strikingly fewer vocalizations were detected in two independent cohorts of 16p11.2 heterozygous deletion males (+/−) during the first exposure to an unfamiliar estrous female, as compared to wildtype littermates (+/+). When the female was removed, +/+ emitted calls, but at a much lower level, whereas +/− males called minimally. Sensory and motor abnormalities were detected in +/−, including higher nociceptive thresholds, a complete absence of acoustic startle responses, and hearing loss in all +/− as confirmed by lack of auditory brainstem responses to frequencies between 8 and 100 kHz. Stereotyped circling and backflipping appeared in a small percentage of individuals, as previously reported. However, these sensory and motor phenotypes could not directly explain the low vocalizations in 16p11.2 deletion mice, since (a) +/− males displayed normal abilities to emit vocalizations when the female was subsequently reintroduced, and (b) +/− vocalized less than +/+ to social odor cues delivered on an inanimate cotton swab. Our findings support the concept that mouse USVs in social settings represent a response to social cues, and that 16p11.2 deletion mice are deficient in their initial USVs responses to novel social cues.

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Behavioral Abnormalities and Circuit Defects in the Basal Ganglia of a Mouse Model of 16p11.2 Deletion Syndrome

Cited by 219 publications

References 61 publications

Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism

Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism

The Emerging Clinical Neuroscience of Autism Spectrum Disorder

16p11.2 Deletion Syndrome Mice Display Sensory and Ultrasonic Vocalization Deficits During Social Interactions

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