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Behavioural phenotyping assays for mouse models of autism

Key Points

  • Autism is a neurodevelopmental disorder that is diagnosed by the presence of three categories of behavioural criteria: first, unusual reciprocal social interactions; second, deficits in communication; and third, stereotyped, repetitive behaviours with restricted interests. Behavioural phenotyping of mouse models of autism requires assays that are relevant to each of the three categories of the core symptoms.

  • Optimal animal models incorporate phenotypes that are analogous to the human disease (face validity). They should also incorporate the same cause as the human disease (construct validity), and ameliorative responses that are specific to treatments that are efficacious in the human disease (predictive validity). Robust phenotypes in mouse models of autism that have face validity and construct validity hold great promise as translational tools for discovering effective therapeutics for components of autism spectrum disorders.

  • Mus musculus is a social species that engages in high levels of reciprocal social interactions. Assays for deficits in sociability include the three-chambered social approach test, the partition test, observer-scored parameters of reciprocal social interactions and tests of social transmission of food preference.

  • Communication in mice is not well understood, but assays to investigate this include olfactory discrimination, urinary scent marking and countermarking, and assays of ultrasonic vocalizations in social settings.

  • Assays for repetitive behaviours and restricted interests in mice include measures of motor stereotypies, repetitive self-grooming and perseverative spatial habits in learning tasks that include the T-maze and Morris water maze.

  • Control parameters that assess general health, motor functions and sensory abilities (for example, olfactory detection of pheromones) are essential for ruling out artefacts that could confound the interpretation of social, communication or repetitive phenotypes.

Abstract

Autism is a heterogeneous neurodevelopmental disorder of unknown aetiology that affects 1 in 100–150 individuals. Diagnosis is based on three categories of behavioural criteria: abnormal social interactions, communication deficits and repetitive behaviours. Strong evidence for a genetic basis has prompted the development of mouse models with targeted mutations in candidate genes for autism. As the diagnostic criteria for autism are behavioural, phenotyping these mouse models requires behavioural assays with high relevance to each category of the diagnostic symptoms. Behavioural neuroscientists are generating a comprehensive set of assays for social interaction, communication and repetitive behaviours to test hypotheses about the causes of austism. Robust phenotypes in mouse models hold great promise as translational tools for discovering effective treatments for components of autism spectrum disorders.

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Figure 1: Reciprocal social interactions.
Figure 2: Automated three-chambered social approach.
Figure 3: Olfactory habituation/dishabituation.
Figure 4: Repetitive self-grooming.

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Acknowledgements

M. L. Scattoni, Istituto Superiore di Sanitá, Rome, Italy, generously contributed the supplementary audio file giving examples of mouse vocalizations. We thank A. Katz, Laboratory of Behavioural Neuroscience, National Institute of Mental Health (NIMH), Bethesda, Maryland, USA, for the outstanding editing of the supplementary movies. J.N.C. is supported by the NIMH Intramural Research Program MH02179. C.L. is supported by NIMH grants R01MH81873, 1RC1MH089721 and 1R01MH089390.

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Correspondence to Jacqueline N. Crawley.

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Supplementary information

Supplementary Movie S1

B6 Reciprocal Social Interactions. (WMV 9857 kb)

41583_2010_BFnrn2851_MOESM2_ESM.pdf

Supplementary Movie S2

B6 Social Approach. (WMV 11809 kb)

41583_2010_BFnrn2851_MOESM4_ESM.pdf

Supplementary Movie S3

Olfactory habituation/dishabituation. (WMV 1185 kb)

41583_2010_BFnrn2851_MOESM6_ESM.pdf

Supplementary Audio S4

Ultrasonic vocalizations emitted by two adult male B6 mice during social interactions. (WAV 2950 kb)

41583_2010_BFnrn2851_MOESM8_ESM.pdf

Supplementary Movie S5.

Repetitive self-grooming. (WMV 3809 kb)

41583_2010_BFnrn2851_MOESM10_ESM.pdf

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FURTHER INFORMATION

Autism Genetic Research Exchange

Autism Speaks

International Mouse Strain Resource

Knockout Mouse Project

Mouse Genome Informatics

Mouse Phenome Project

National Database for Autism Research

National Institute of Mental Health Autism Spectrum Disorders Public Information

National Institutes of Health Autism Coordinating Committee

Simons Foundation Autism Research Initiative

Simons Foundation Simplex Collection (genetic resource)

Glossary

Nesting

Building nests in the home cage and sleeping together in a huddle in the home cage.

Social memory

Time-delayed recognition of a familiar mouse.

Social affiliation

Social affiliation behaviours in mice include parent–pup interactions, male–female pair bonding, mating and aggression.

Social recognition

Social recognition is the ability to distinguish familiar from novel conspecifics. Social recognition by a subject mouse is defined by reduced social approach or reduced time spent investigating a familiar partner and reinstatement of investigation when a novel partner is introduced.

Y-maze

A three-armed runway in the shape of the letter Y, used to measure exploratory behaviours in rodents.

Repetitive self-grooming

Unusually long duration of the normal pattern of grooming of the entire body.

T-maze

A device used to examine spatial position habit. Subject mice are trained on an appetitive task with a spatially contingent reinforcer. Failure of the subject to switch from a previously learned location to a new location represents resistance to change in routine.

Morris water maze

A device used to test spatial learning. Subject mice navigate a pool of water and utilize distal spatial cues to locate a hidden escape platform. Failure of the subject to switch from a previously learned location to a new location models resistance to change in routine.

Attentional set-shift task

An attentional task that requires the subject to simultaneously discriminate in two dimensions to obtain food reinforcement. For example, the food may be buried in sand versus gravel, and contained in a round bowl versus a square box. This task is dependent on intact frontal cortex functions and may be analogous to executive function tasks in humans.

Five-choice serial reaction time test

A rodent attentional task analogous to sustained attention tasks for humans. The mouse must monitor five spatial locations simultaneously and nose-poke when the light above one is illuminated to obtain the food reinforcer. Accuracy and speed of response measure attentional performance. Distractors may be added to evaluate attentional shift.

Elevated plus-maze

A device used to examine the naturalistic conflict between the tendency of mice to explore a novel environment and the aversive properties of an open elevated runway. Mice generally prefer the two enclosed arms, but will explore the two open arms to some extent. The total number of entries into all arms serves as a control for general locomotion. For example, motor dysfunctions or sedative effects of a drug treatment will reduce total arm entries.

Applied behaviour analysis

An empirically validated teaching strategy that consists of a systematic process of studying and modifying observable behaviour, using environmental manipulations and behavioural response tracking to improve relevant behaviours.

Pivotal response training

An intervention using a structured environment that includes items and activities that the affected individual prefers, and that can be used to meet goals. Each learning interaction consists of the therapist offering choices, the individual making a choice and the therapist requiring an appropriate response in order for the individual to gain access to the item or activity.

Social peer enrichment

Rearing and housing mice with social cagemates.

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Silverman, J., Yang, M., Lord, C. et al. Behavioural phenotyping assays for mouse models of autism. Nat Rev Neurosci 11, 490–502 (2010). https://doi.org/10.1038/nrn2851

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