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

Auditory Processing Enhancements in the TS2-Neo Mouse Model of Timothy Syndrome, a Rare Genetic... Timothy syndrome (TS) is a rare genetic disorder caused by a single de novo missense mutation to the 8A exon of CACNA1C gene, which codes for the voltage-gated L-type Ca2+ channel (Cav1.2). TS is strongly associated with cardiac arrthytmias, autism spectrum disorders (ASDs), and neurological dysfunction such as language impairments, seizures, and intellectual disability. A genetically engineered knock-in mouse with a heterogeneous TS2 (G406R) mutation in the L-type calcium channel containing a neomycin resistance cassette was developed to study ASD-like behaviors. This mouse model (TS2-neo) provides us with a platform to investigate the role of calcium channel inactivation and calcium signaling related to brain development and ASD. The purpose of the current study was to behaviorally characterize TS2-neo mice by assessing their performance on a wide variety of behavioral paradigms, including replication of findings that support the TS2-neo as a valid platform for studying ASD-like behavior. In addition to examining core social and repetitive anomalies, we sought to focus on basic perceptual processing in the auditory domain. Results indicate that the loss of Cav1.2 inactivation in this mouse model results in deviant social and repetitive behaviors as well as poor sensorimotor learning. Additionally, TS2-neo mice display superior performance on both an embedded tone and silent gap discrimination task for short-duration acoustic stimuli. These findings parallel the low-level auditory enhancements observed within the ASD clinical population. Additionally, structural anomalies were seen for mutant mice in some white matter tracts and in the medial geniculate nucleus (MGN). Co-occurrence of these findings suggests that aberrant MGN morphology may be related to enhanced auditory processing phenotype as seen in ASD. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Advances in Neurodevelopmental Disorders Springer Journals

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

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Publisher
Springer International Publishing
Copyright
Copyright © 2017 by Springer International Publishing
Subject
Psychology; Developmental Psychology; Psychiatry; Social Work; Child and School Psychology; Public Health; Neurosciences
ISSN
2366-7532
eISSN
2366-7540
D.O.I.
10.1007/s41252-017-0029-1
Publisher site
See Article on Publisher Site

Abstract

Timothy syndrome (TS) is a rare genetic disorder caused by a single de novo missense mutation to the 8A exon of CACNA1C gene, which codes for the voltage-gated L-type Ca2+ channel (Cav1.2). TS is strongly associated with cardiac arrthytmias, autism spectrum disorders (ASDs), and neurological dysfunction such as language impairments, seizures, and intellectual disability. A genetically engineered knock-in mouse with a heterogeneous TS2 (G406R) mutation in the L-type calcium channel containing a neomycin resistance cassette was developed to study ASD-like behaviors. This mouse model (TS2-neo) provides us with a platform to investigate the role of calcium channel inactivation and calcium signaling related to brain development and ASD. The purpose of the current study was to behaviorally characterize TS2-neo mice by assessing their performance on a wide variety of behavioral paradigms, including replication of findings that support the TS2-neo as a valid platform for studying ASD-like behavior. In addition to examining core social and repetitive anomalies, we sought to focus on basic perceptual processing in the auditory domain. Results indicate that the loss of Cav1.2 inactivation in this mouse model results in deviant social and repetitive behaviors as well as poor sensorimotor learning. Additionally, TS2-neo mice display superior performance on both an embedded tone and silent gap discrimination task for short-duration acoustic stimuli. These findings parallel the low-level auditory enhancements observed within the ASD clinical population. Additionally, structural anomalies were seen for mutant mice in some white matter tracts and in the medial geniculate nucleus (MGN). Co-occurrence of these findings suggests that aberrant MGN morphology may be related to enhanced auditory processing phenotype as seen in ASD.

Journal

Advances in Neurodevelopmental DisordersSpringer Journals

Published: Jul 1, 2017

References

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