Mouse models of autism spectrum disorders: the challenge for behavioral genetics

American Journal of Medical Genetics Part C (Semin. Med. Genet.) 142C:40 – 51 (2006) Mouse Models of Autism Spectrum Disorders:The Challenge for Behavioral Genetics SHERYL S. MOY,* JESSICA J. NADLER, TERRY R. MAGNUSON, AND JACQUELINE N. CRAWLEY Autism is a severe neurodevelopmental disorder, which typically emerges early in childhood. The core symptomsof autism include deficits in social interaction, impaired communication, and aberrant repetitive behavior,including self-injury. Despite the strong genetic component for the disease, most cases of autism have not beenlinked to mutations in a specific gene, and the etiology of the disorder has yet to be established. At the presenttime, there is no generally accepted therapeutic strategy to treat the core symptoms of autism, and there remainsa critical need for appropriate animal models and relevant behavioral assays to promote the understanding andtreatment of the clinical syndrome. Challenges for the development of valid mouse models include complexgenetic interactions underlying the high heritability of the disease in humans, diagnosis based on deficits in socialinteraction and communication, and the lack of confirmatory neuropathological markers to provide validation forgenetic models of the disorder. Research focusing on genes that mediate social behavior in mice may help identifyneural circuitry essential for normal social interaction, and lead to novel genetic animal models of the autismbehavioral phenotype.
KEY WORDS: autism; fragile X; mice; repetitive behavior; Rett syndrome; social interaction and communication deficits, rather than a aberrations characteristic of human clin- ed in an animal. In addition, the ASDs are cellular function, and therapeutic efficacy munication, as well as aberrant repetitive ical and theoretical issues in their beha- children demonstrate rigid adherenceto routines and restricted interests, oftenforming obsessional preoccupations with Sheryl S. Moy, Ph.D., is the Associate Director of the Mouse Behavioral Phenotyping Laboratory of the Neurodevelopmental Disorders Research Center, and an Associate Professor in the Department of Psychiatry at UNC. Dr. Moy’s work focuses on the development of mouse models ic responses, such as tic-like stereotypies relevant to human clinical disorders, including autism and schizophrenia.
Jessica J. Nadler, Ph.D., is a Postdoctoral Fellow in the Department of Genetics at UNC.
Dr. Nadler works on identifying the underlying gene expression changes associated with deficits Terry R. Magnuson, Ph.D., is the Chair of the UNC Department of Genetics and Director of the Carolina Center for Genome Sciences.
Jacqueline N. Crawley, Ph.D., is Director of the Laboratory of Behavioral Neuroscience at NIMH and the Mouse Behavioral Phenotyping Laboratory of the Neurodevelopmental Disorders Research Center at UNC. Modeling neuropsychiatric disorders using mouse behavioral geneticsrepresents a theme of Dr. Crawley’s research program.
Grant sponsor: STAART; Grant number: U54 MH66418; Grant sponsor: MRDDRC; Grant number: P30 HD03110; Grant sponsor: NIMH Intramural Research Program.
*Correspondence to: Sheryl S. Moy, Neurodevelopmental Disorders Research Center, CB no.
7146, University of North Carolina, Chapel Hill, NC 27599-7146. E-mail: disorders [Gillberg and Billstedt, 2000].
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMIN. MED. GENET.): DOI 10.1002/ajmg.c autistic subjects may have various altera- ing susceptibility in a non-deterministic tions in brain size and neuroanatomy.
involved in autism susceptibility include size and brain volume [Piven et al., 1996; 1999; Saitoh et al., 2001], and decreased [Bailey et al., 1998; Palmen et al., 2004].
technology, mouse geneticists are able to tion, a serious drawback of this approach consistent with the allele present in the associated alleles for a given disorder, and ways thought to be altered in autism.
more frequently in males than in females, investigated when evaluating the validity used to identify various candidate genes, mon allele found in fragile X patients is basis for Rett disorder; [Shibayama et al., 10% (e.g., Barton and Volkmar [1998]).
fragile X, the number of these repeats is modification is to generate a null allele, the deficits observed in the disease, but AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMIN. MED. GENET.): DOI 10.1002/ajmg.c TABLE I. Genes Linked to Autism and the Relevant Mouse Models Genes for neurodevelopmental disorders associated with autism Nf1-null, heterozygous, and NF123aÀ/À mouse Other genes that may contribute to autism susceptibility Wnt2-null mouseDvl1 (Dishevelled-1)-null mouse Chiurazzi, 2001; Darnell et al., 2005].
also Paradee et al., 1999]. These differ- human disorders associated with autism.
late complex behavioral phenotypes,even in a defined, single-locus disease.
also reflects symptoms associated withthe human disorder. The null mice sequence is likely similar: severe reduction are two global methods of transcriptional attributed, in part, to the effect of the mice. In particular, the Fmr1-null allele AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMIN. MED. GENET.): DOI 10.1002/ajmg.c truncation often leads to a classical Rett cations are associated with the preserved of the Mecp2 locus can lead to deficits in social interaction [Moretti et al., 2005].
and enhanced susceptibility for seizures, of the mutation [Jiang et al., 1998; Miura (NF1), an autosomal dominant disordercharacterized by cognitive and language deficits, poor motor skills, and tumors of the peripheral nerves [Silva et al., 1997; testing of heterozygotes has revealed that tion for tumors [Silva et al., 1997; Costa origin), the phenotype of these deletions [Chen et al., 2001; Guy et al., 2001].
targeted disruption have delayed onset of terol biosynthesis, suggesting a possible in mice leads to severe respiratory failure protein’s role in the disease process can [Fitzky et al., 2001; Wassif et al., 2001; neural tissue, rather than in the periph- ery. Another allele, Mecp2308, is similar tuberous sclerosis 1, is characterized by AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMIN. MED. GENET.): DOI 10.1002/ajmg.c region of human chromosome 7p14.2-15. A polymorphism changing a histi- susceptibility for autism [e.g., Collabo- the population [Ingram et al., 2000].
rative Linkage Study of Autism, 1999].
allele for Sert is placed on a 129S6 strain cal signal transduction cascade, utilizing screened for autistic-like behaviors [see a premise supported by the identification for the null allele for Maoa have increased with elevated levels of serotonin in blood trations in the brain [Cases et al., 1995].
Pups exhibit trembling, difficulty right- and Leventhal, 1996]. Clinical trials have Wassink et al., 2001]. A null allele of the conditioned fear task [Kim et al., 1997], test [Popova et al., 2000]. Overall, Sert- significant behavioral effects of altera- interaction deficits [Lijam et al., 1997; ses in brain serotonin levels [Bengel et al., et al., 2004]. A targeted disruption of the foliation of the cerebellum [Joyner et al., Reeler brains revealed that neurons failed AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMIN. MED. GENET.): DOI 10.1002/ajmg.c wire cage, which allows visual, auditory, association is not observed in all autism tions. An identical wire cage is placed in [Rodier, 1996; Insel, 2001; Murcia et al., symptoms characteristic of the ASDs.
clinicians, therapists, and other profes- ding schizophrenia, bipolar disorder, and sionals working in the field of autism, has depression, as well as with lissencephaly [Fatemi, 2001], suggesting that the Reeler to model specific aspects of autistic-like and in males and females [Brodkin et al., brain alterations specific to autism. Apart preference for social novelty. In this case, preference for social novelty, and learn- the unfamiliar mouse from the first phase maze task [Salinger et al., 2003; Lalonde et al., 2004]. Some studies have reported the opposite side of the test box. We have tasks that may be relevant to elements of demonstrate a shift in preference, so that stranger 2, rather than the more-familiar between two unfamiliar conspecifics.
nent for our behavioral testing battery.
avoidance, using a relatively rapid, auto- mated task [Nadler et al., 2004]. Further utilize observations of social interaction resident-intruder paradigm, or tube tests gene-dosage relationship [Salinger et al., titative evaluation of social approach and the first phase of this test, mice are given ses to social isolation early in develop- AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMIN. MED. GENET.): DOI 10.1002/ajmg.c TABLE II. Mouse Behavioral Tasks for Modeling the Autism Phenotype Lijam et al. [1997]; Moretti et al. [2005] Mohn et al. [1999]; Moretti et al. [2005] Holtzman et al. [1996]; Moles et al. [2004] Restricted interests, repetitive behavior; Wu and Melton [1993]; Presti et al. [2003] DeLorey et al. [1998]; Turner et al. [2001] Salinger et al. [2003]; Yan et al. [2004] Griebel et al. [2000]; Ren-Patterson et al. [2005] Bouwknecht and Paylor [2002]; Peier et al. [2000] Tuetling et al. [1999]; Nielson et al. [2002] Martinez-Cue et al. [1999]; Long et al. [2004] Lalonde et al. [2004]; Moretti et al. [2005] Gerlai et al. [1996]; Miura et al. [2002] Morris water maze, hidden platform task Sago et al. [1998]; Lalonde et al. [2004]Radial arm maze Driscoll et al. [2004]; Frankland et al. [2004] DeLorey et al. [1998]; Lira et al. [2003] escape platform before a final probe trial.
rewards. One disadvantage of this task is perseverative sniffing, circling, digging, testing, the escape platform is placed in of motivational levels across strains.
ing [Cases et al., 1995; Homanics et al., grooming and scratching can lead to self- injury, such as torn ears and skin lesions tion during reversal learning could serve vior include measures of exploration on a during the reversal phase [Bakker et al., in an excessive adherence to routine.
pokes into a restricted set of holes, versus Bell et al., 2003], and the investigation of resistance to change a learned pattern of behavior. In this task, mice are trained to locate a hidden escape platform, which is particular arm (left or right) of the maze periphery of the pool. Spatial learning in AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMIN. MED. GENET.): DOI 10.1002/ajmg.c can result in a less severe phenotype.
global view of the etiology of autism.
be changed in mouse models for ASDs.
trol measures, such as tests for activity vasopressin deficient mice [Insel et al., crucial for the interpretation of observed deficits in social preference [Moy et al., and paternal, present in the genome.
2004], as well as other tasks relevant to the appropriate parent [e.g., Jiang et al., 1998; Miura et al., 2002; Liljelund et al., appears to underlie susceptibility for the described in this review involve targeted across background strains, as observed in the Engrailed mouse, Joyner et al., 1991; disadvantage of this approach is that the consider strain characteristics when gen- for detailed genetic characterization.
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October 2006 Editorial Olivier Forcade, president of the Academic Council and the Board of Administrators of the EFEO for the past four years, has recently been elected to the Chair of Contemporary History at Amiens University. He is leaving his responsibilities for the French Institutes Abroad at the Ministry of Higher Education and Research. The EFEO is deeply indebted to Mr. Forcade,


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