RGD Reference Report - Altered Auditory Processing, Filtering, and Reactivity in the Cntnap2 Knock-Out Rat Model for Neurodevelopmental Disorders. - Rat Genome Database

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Altered Auditory Processing, Filtering, and Reactivity in the Cntnap2 Knock-Out Rat Model for Neurodevelopmental Disorders.

Authors: Scott, Kaela E  Schormans, Ashley L  Pacoli, Katharine Y  De Oliveira, Cleusa  Allman, Brian L  Schmid, Susanne 
Citation: Scott KE, etal., J Neurosci. 2018 Oct 3;38(40):8588-8604. doi: 10.1523/JNEUROSCI.0759-18.2018. Epub 2018 Aug 20.
RGD ID: 126790476
Pubmed: (View Article at PubMed) PMID:30126973
DOI: Full-text: DOI:10.1523/JNEUROSCI.0759-18.2018

Sensory processing, and auditory processing in particular, is altered in individuals with neurodevelopmental disorders such as autism spectrum disorders (ASDs). The typical maturation of the auditory system is perturbed in these individuals during early development, which may underlie altered auditory reactivity that persists in later life. Of the many genes that regulate the auditory system development, loss-of-function mutations in the CNTNAP2 gene are strongly associated with language processing deficits and ASD. Therefore, using a novel Cntnap2 knock-out rat model, we tested the impact of Cntnap2 loss on auditory processing, filtering, and reactivity throughout development and young adulthood in male and female animals. Although hearing thresholds were not altered in Cntnap2 knock-out animals, we found a reduction in response amplitudes and a delay in response latency of the auditory brainstem response (ABR) in juvenile Cntnap2 knock-out rats compared with age-matched controls. Amplitudes and latency of the ABR largely normalized by adulthood, indicating a delayed maturation of auditory processing pathways in Cntnap2 knock-out rats. Despite the reduced ABR amplitudes, adolescent Cntnap2 knock-out animals displayed increased startle reactivity accompanied by disruptions in sensory filtering and sensorimotor gating across various conditions, most of which persisted in adulthood. All of these observations show striking parallels to disruptions reported in ASD. Our results also imply that developmental disruptions of sensory signal processing are associated with persistent changes in neural circuitries responsible for implicit auditory evoked behavior, emphasizing the need for interventions that target sensory processing disruptions early during development in ASD.SIGNIFICANCE STATEMENT This is the first study of brainstem auditory processing in a novel knock-out rat model with very high construct and face validity for autism spectrum disorders. Electrophysiological and behavioral measures of implicit auditory-evoked responses were systematically taken across developmental stages. Auditory processing, filtering, and reactivity disruptions show striking similarities to observations in autism. We also show for the first time that, whereas auditory brainstem responses normalize by adulthood, disruptions in brainstem-mediated auditory-evoked behavior persist. This indicates that early developmental perturbations in sensory processing can cause permanent maladaptive changes in circuitries responsible for auditory reactivity, underlining the importance for interventions early during development aiming at normalizing sensory processing.

Disease Annotations    

Gene Ontology Annotations    

Biological Process

Phenotype Annotations    

Mammalian Phenotype
Objects Annotated

Genes (Rattus norvegicus)
Cntnap2  (contactin associated protein 2)
Cntnap2em1Sage  (contactin associated protein-like 2; zinc finger nuclease induced mutant 1, Sigma Advanced Genetic Engineering Labs)

Genes (Mus musculus)
Cntnap2  (contactin associated protein-like 2)

Genes (Homo sapiens)
CNTNAP2  (contactin associated protein 2)

SD-Cntnap2em1Sage  (NA)

Additional Information