Elsevier

Behavioural Brain Research

Volume 251, 15 August 2013, Pages 18-24
Behavioural Brain Research

Research report
Rats selectively bred for low levels of play-induced 50 kHz vocalizations as a model for Autism Spectrum Disorders: A role for NMDA receptors

https://doi.org/10.1016/j.bbr.2013.04.022Get rights and content

Highlights

  • The NMDA receptor complex plays a functional role in autism.

  • Rats bred for low rates of hedonic ultrasonic calls show an autistic-like phenotype.

  • GLYX-13, a NMDAR glycine-site functional partial agonist, rescues this autistic-like phenotype.

  • GLYX-13 may have therapeutic potential for the treatment of autism.

Abstract

Early childhood autism is characterized by deficits in social approach and play behaviors, socio-emotional relatedness, and communication/speech abnormalities, as well as repetitive behaviors. These core neuropsychological features of autism can be modeled in laboratory rats, and the results may be useful for drug discovery and therapeutic development. We review data that show that rats selectively bred for low rates of play-related pro-social ultrasonic vocalizations (USVs) can be used to model social deficit symptoms of autism. Low-line animals engage in less social contact time with conspecifics, show lower rates of play induced pro-social USVs, and show an increased proportion of non-frequency modulated (i.e. monotonous) ultrasonic vocalizations compared to non-selectively bred random-line animals. Gene expression patterns in the low-line animals show significant enrichment in autism-associated genes, and the NMDA receptor family was identified as a significant hub. Treatment of low-line animals with the NMDAR functional glycine site partial agonist, GLYX-13, rescued the deficits in play-induced pro-social 50-kHz USVs and reduced monotonous USVs. Since the NMDA receptor has been implicated in the genesis of autistic symptoms, it is possible that GLYX-13 may be of therapeutic value in the treatment of autism.

Section snippets

Vocal communication in mammals relevant to autism

Vocal communications in mammalian species, especially emotion related forms, have been at the center of research interest for decades because of its complex neural control, biological importance of transfer of information and regulation of behavior, as well as pertinence to the question of their social-emotional processes [1], [2], [3], [4] as well as human speech and language evolved [5], [6], [7]. Some of the early work on the neurochemical control of separation-calls of mammals and birds,

Selective breeding for low and high emission of appetitive 50 kHz vocalizations

Selective breeding of Long–Evans rats for low and high levels of play-induced 50 kHz vocalizations was based on heterospecific play of juvenile rats with the human hand (dubbed “tickling”) [33], [36], [62]. Tickling play, which resembles natural rough-and-tumble play of juveniles, was found to have highly rewarding properties for rats [62] and caused emission of high numbers of 50 kHz vocalizations during the play. Rats were subjected to 2-min tickle play tests consisting of four cycles of 15 s

NMDA receptors play a functional role in autism

Among many transmitter systems, glutamatergic NMDA receptors have been implicated in etiopathology of several neuropsychiatric disorders including neurodevelopmental disorders such as ASD [75]. The NMDA receptor family was also identified as a significant ASD hub [12], i.e., genes having a greater number of protein-protein interactions with other autism candidate genes. Recently, the glutamatergic receptor family, particularly N-methyl-d-aspartate receptors (NMDAR), have become of interest as

In Conclusion: autistic-like animal phenotypes and drug discovery.

Future developments in preclinical modeling of psychiatric disorders will need to take the affective feelings of animals ever more seriously, since the data-base is substantial that all animals homologously share certain fundamental emotional feelings that evolved long before the human line diverged from other mammals [10], [93]. Although it is foolish to suggest that these ancestral feelings are identical across species, the evolutionary continuities at neuroanatomical, neurochemical and basic

Acknowledgments

This research was supported by grants from the Ralph and Marian Falk Medical Research Trust (Chicago, IL) to JRM, Hope for Depression Research Foundation to JSB, JRM, SMB, JP and NIMH R01-MH094835 to JSB. We would like to thank the Northwestern University Behavioral Phenotyping Core for it's assistance, and Ms Mary Schmidt for her expert technical assistance.

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