Mouse Models of Autism Spectrum Disorders: The Challenge for Behavioral Genetics
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American Journal of Medical Genetics Part C (Semin. Med. Genet.) 142C:40 –51 (2006)
A R T I C L E
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 symptoms
of 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 been
linked to mutations in a specific gene, and the etiology of the disorder has yet to be established. At the present
time, there is no generally accepted therapeutic strategy to treat the core symptoms of autism, and there remains
a critical need for appropriate animal models and relevant behavioral assays to promote the understanding and
treatment of the clinical syndrome. Challenges for the development of valid mouse models include complex
genetic interactions underlying the high heritability of the disease in humans, diagnosis based on deficits in social
interaction and communication, and the lack of confirmatory neuropathological markers to provide validation for
genetic models of the disorder. Research focusing on genes that mediate social behavior in mice may help identify
neural circuitry essential for normal social interaction, and lead to novel genetic animal models of the autism
behavioral phenotype. ß 2006 Wiley-Liss, Inc.
KEY WORDS: autism; fragile X; mice; repetitive behavior; Rett syndrome; social interaction
INTRODUCTION challenging. For example, the diagnostic AUTISM CLINICAL
criteria for autism are based on social DISORDER
Advances in the fields of genetics and and communication deficits, rather than a
molecular biology have led to the general neurological pathology or neu- Diagnostic and Neuropathological
creation of mouse models with genetic rochemical marker that could be model- Features
aberrations characteristic of human clin- ed in an animal. In addition, the ASDs are
Diagnosis of autism is based on beha-
ical disorders. These models can be characterized by marked genetic and
vioral symptomatology. The defining
tremendously beneficial for determining phenotypic heterogeneity, suggesting
characteristics include attenuated or
disease etiology, effects on organic and that single-gene mouse mutants may not
abnormal social interaction and com-
cellular function, and therapeutic efficacy provide a model for the intrinsic com- munication, as well as aberrant repetitive
of novel treatment strategies. However, plexity of these diseases. This review
behavior, with symptoms emerging
the development of mouse models for describes current genetic mouse models
early in childhood [American Psychia-
the autism spectrum disorders (ASDs), for the ASDs, and discusses methodolog-
tric Association, 1994]. In addition to
including autism, Asperger disorder, and ical and theoretical issues in their beha-
significant language deficits, autistic
Rett syndrome, has proven especially vioral phenotyping and use.
children demonstrate rigid adherence
to routines and restricted interests, often
forming obsessional preoccupations with
Sheryl S. Moy, Ph.D., is the Associate Director of the Mouse Behavioral Phenotyping Laboratory specific objects or topics. The autism
of the Neurodevelopmental Disorders Research Center, and an Associate Professor in the phenotype also includes unusual motor-
Department of Psychiatry at UNC. Dr. Moy’s work focuses on the development of mouse models
relevant to human clinical disorders, including autism and schizophrenia.
ic responses, such as tic-like stereotypies
Jessica J. Nadler, Ph.D., is a Postdoctoral Fellow in the Department of Genetics at UNC. and self-injury [Bodfish et al., 2000],
Dr. Nadler works on identifying the underlying gene expression changes associated with deficits impaired motor function, and abnormal
in social and cognitive behaviors.
Terry R. Magnuson, Ph.D., is the Chair of the UNC Department of Genetics and Director of the
responses to sensory stimuli [Baranek,
Carolina Center for Genome Sciences. 2002]. Mental retardation is observed in
Jacqueline N. Crawley, Ph.D., is Director of the Laboratory of Behavioral Neuroscience at NIMH the majority of children diagnosed with
and the Mouse Behavioral Phenotyping Laboratory of the Neurodevelopmental Disorders
Research Center at UNC. Modeling neuropsychiatric disorders using mouse behavioral genetics
autism, and seizures are present in an
represents a theme of Dr. Crawley’s research program. estimated 30% of the autistic population
Grant sponsor: STAART; Grant number: U54 MH66418; Grant sponsor: MRDDRC; Grant [Gillberg and Billstedt, 2000]. Other
number: P30 HD03110; Grant sponsor: NIMH Intramural Research Program.
*Correspondence to: Sheryl S. Moy, Neurodevelopmental Disorders Research Center, CB no.
symptoms reported in autism include
7146, University of North Carolina, Chapel Hill, NC 27599-7146. E-mail: ssmoy@med.unc.edu anxiety [Muris et al., 1998], and sleep
DOI 10.1002/ajmg.c.30081 disorders [Gillberg and Billstedt, 2000].
ß 2006 Wiley-Liss, Inc.ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMIN. MED. GENET.): DOI 10.1002/ajmg.c 41
Investigators have reported that polymorphisms for the disease conferr- protein. Mouse models based on tar-
autistic subjects may have various altera- ing susceptibility in a non-deterministic geted disruption of genes that may be
tions in brain size and neuroanatomy. way [Folstein and Rosen-Sheidley, involved in autism susceptibility include
These differences include increased head 2001; Keller and Persico, 2003]. the Fmr1-null mouse, a model for fragile
size and brain volume [Piven et al., 1996; X syndrome [Bakker et al., 1994],
Bailey et al., 1998; Courchesne et al., Gabrb3- and Ube3a-null mice, models
MOUSE MODELS FOR
2001], decreased volume of hippocam- for Angelman syndrome [DeLorey et al.,
AUTISM SPECTRUM
pus, amygdala, and corpus callosum 1998; Jiang et al., 1998], the DHCR7-
DISORDERS
[Piven et al., 1997; Aylward et al., null mouse, a model for Smith–Lemli–
1999; Saitoh et al., 2001], and decreased Optiz syndrome [Fitzky et al., 2001],
Candidate Gene Approach
numbers of Purkinje cells in cerebellum and the Dvl1-null mouse [Lijam et al.,
[Bailey et al., 1998; Palmen et al., 2004]. With the advent of embryonic stem cell 1997] (Table I).
Neuroimaging assessment of regional technology, mouse geneticists are able to While a targeted disruption can pro-
brain function has demonstrated defic- generate mouse models carrying the vide clues on the role of the protein in
ient or abnormal activity in frontal and targeted disruption or mutation of normal brain development and func-
temporal cortex [Happé et al., 1996; specific candidate genes. However, in tion, a serious drawback of this approach
Schultz et al., 2000]. Unfortunately, the case of the ASDs, determination of is that the null allele may not be
many of the findings on neuropatholo- which genes to target has proven consistent with the allele present in the
gical changes in autism have not proven problematic. Research in human popu- ASD population. A second approach for
to be consistent across studies, or have lations suggests that the number of loci creating relevant animal models is to
unknown functional ramifications, such associated with autism exceeds 15 engineer an allele known to be disease-
as the behavioral consequences of in- [Risch et al., 1999]. Most mouse models associated in humans. This modification
creased brain size. for the ASDs have been based on may be more likely to mimic the
manipulations of loci that mediate molecular nature of the disease. How-
single-gene human disorders character- ever, there are often several disease-
Genetic Component of Autism
ized by autistic symptoms, or that have associated alleles for a given disorder, and
While the etiology of autism is not yet been identified through association or it can be unclear which allele to
known, support for a strong genetic linkage studies in human genetics. Other generate. The mouse models of ASDs
component is evident from the 70% to mouse models involve mutations in path- discussed below represent both targeted-
80% concordance between monozygo- ways thought to be altered in autism. disruption and disease-associated types
tic twins [Folstein and Rosen-Sheidley, of approaches and it is important to
2001]. Autism occurs about four times understand which type of allele is being
more frequently in males than in females, investigated when evaluating the validity
although this rate varies within subpop- Most mouse models for the of the model.
ulations [Fombonne, 2002; Keller and ASDs have been based on
Persico, 2003]. Association studies and
manipulations of loci that Mouse Model for
familial linkage analyses have been
mediate single-gene human Fragile X Syndrome
used to identify various candidate genes,
including WNT2 [Wassink et al., 2001], disorders characterized by Fragile X syndrome is characterized by
GABRB3 [Buxbaum et al., 2002], mental retardation, physical abnormal-
UBE3A [Nurmi et al., 2001], and autistic symptoms, or that ities, and, in most cases, autistic-like
RELN [Persico et al., 2001]. The autism have been identified through behavior [Hagerman et al., 1986]. The
phenotype is also associated with muta- disease was mapped to a single locus on
tions in FMR1 (the underlying abnorm-
association or linkage studies in the X chromosome, Fragile X Mental
ality in fragile X syndrome; [Hagerman human genetics. Other mouse Retardation 1 (FMR1). The most com-
et al., 1986]) and MECP2 (the genetic models involve mutations in mon allele found in fragile X patients is
basis for Rett disorder; [Shibayama et al., an expansion of a trinucleotide repeat
2004]). However, the percentage of pathways thought to be altered [Kremer et al., 1991]. In a normal FMR1
autism cases that can be linked to a in autism. allele, there are about 40 repeats of a
known genetic aberration is only around CCG nucleotide motif. In patients with
10% (e.g., Barton and Volkmar [1998]). fragile X, the number of these repeats is
Overall, studies suggest the autism The most common strategy for genetic dramatically increased, leading to the
phenotype cannot be attributed to a modification is to generate a null allele, severe reduction of FMR1 protein
single gene. Rather, the clinical syn- or targeted disruption, which deletes a (FMRP) expression. It is not known
drome results from multiple genes inter- portion of the locus, and generally how the loss of FMRP in brain leads to
acting together, with some genetic prevents the production of functional the deficits observed in the disease, but42 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMIN. MED. GENET.): DOI 10.1002/ajmg.c ARTICLE
TABLE I. Genes Linked to Autism and the Relevant Mouse Models
Candidate gene Genetic mouse model
Genes for neurodevelopmental disorders associated with autism
FMR1 (Fragile X syndrome) Fmr1-null mouse
MECP2 (Rett syndrome) Mecp2-null mouse, Mecp2308/Y mouse
GABRB3, UBE3A (Angelman’s syndrome) Gabrb3-null mouse
Ube3a-null mouse
NF1 (Neurofibromatosis type 1) Nf1-null, heterozygous, and NF123a/ mouse
DHCR7 (Smith–Lemli–Opitz syndrome) Dhcr7-null and heterozygous mouse
TSC1, TSC2 (Tuberous sclerosis) Tsc1-null mouse
Other genes that may contribute to autism susceptibility
WNT2 Wnt2-null mouse
Dvl1 (Dishevelled-1)-null mouse
EN2 En1 and En2 (Engrailed) null mouse
HOXA1, HOXA2 Hoxa1-null mouse
SERT (SLC6A4) Sert-null and heterozygous mouse
MAOA Maoa-null mouse
RELN Reln-null and heterozygous mouse
recent work suggests that normal FMRP normal performance is observed when
including altered dendritic
plays a role in RNA binding and the same mutation occurs on a C57BL/
regulating its translation [Oostra and spine morphology and 6J background [Dobkin et al., 2000; see
Chiurazzi, 2001; Darnell et al., 2005]. macroorchidism, similar to also Paradee et al., 1999]. These differ-
The Fmr1-null mouse is one of the ences suggest that there are multiple
best characterized animal models for changes in fragile X patients. genetic interactions, which can modu-
human disorders associated with autism. late complex behavioral phenotypes,
even in a defined, single-locus disease.
Comery et al., 1997]. The behavioral
The Fmr1-null mouse is one phenotype of the fragile X-model mice
Mouse Models for Rett Syndrome
of the best characterized animal also reflects symptoms associated with
the human disorder. The null mice Like fragile X syndrome, Rett syndrome
models for human disorders show cognitive deficits, evidenced by maps to the X chromosome. The disease
associated with autism. impaired performance on reversal learn- is observed primarily in females, with
ing in the Morris water maze [Bakker symptoms including mental retardation,
et al., 1994; Kooy et al., 1996], and slowed growth rate, hypoactivity, and
While the targeted disruption in this altered sensitivity to acoustic stimuli autistic-like behavior. Mutations in a
model is not the same as the common [Chen and Toth, 2001; Nielson et al., single gene, methyl-CpG-binding pro-
human allele at the DNA level, the con- 2002; Frankland et al., 2004]. The mice tein-2 (MECP2), account for the major-
sequence is likely similar: severe reduction also demonstrate changes in social beha- ity of Rett syndrome cases [Amir et al.,
or absence of the FMR1 gene product vior, suggestive of enhanced social 1999]. As its name implies, MECP2
(see Yan et al. [2004]). FMRP-deficient anxiety [Spencer et al., 2005]. However, protein binds to methylated CpG islands
mice demonstrate cytoarchitectonic and some studies have found normal beha- in genomic DNA. MECP2 also associ-
physiological aberrations, including al- vioral responses after disruption of the ates with a protein complex containing
tered dendritic spine morphology and Fmr1 gene [Fisch et al., 1999; Peier histone deacetylase 1. Since DNA
macroorchidism, similar to changes in et al., 2000; Nielson et al., 2002; Yan methylation and histone deacetylation
fragile X patients [Bakker et al., 1994; et al., 2004]. These differences may be are two global methods of transcriptional
attributed, in part, to the effect of the repression, the MECP2 protein con-
different genetic backgrounds of the nects two major methods of down-
FMRP-deficient mice mouse strains used for the Fmr1-null regulating gene expression throughout
mice. In particular, the Fmr1-null allele the mammalian genome [Nan et al.,
demonstrate cytoarchitectonic on a mixed FVB/129 background leads 1998]. Alleles found in the patient
and physiological aberrations, to deficits in spatial learning, while population include missense mutations,ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMIN. MED. GENET.): DOI 10.1002/ajmg.c 43
which cause amino acid changes in the mice show increased anxiety-like beha- gous for the Gabrb3 deletion have
MECP2 protein [Amir et al., 1999; Wan vior, stereotypic forelimb movements significantly reduced levels of the beta
et al., 1999], and nonsense mutations [Shahbazian et al., 2002], and altered 3 subunit in brain, dependent upon both
that result in production of a truncated home-cage and social behavior [Moretti the parent of origin and gender, but do
protein [Zappella et al., 2001]. Early et al., 2005]. In particular, Mecp2308/Y not show seizures or hyperactivity [Lil-
truncation often leads to a classical Rett mice spend less time investigating an jelund et al., 2005]. Ube3a-null mice
syndrome phenotype, while later trun- unfamiliar mouse, in comparison to demonstrate poor rotarod performance,
cations are associated with the preserved normal mice, suggesting that mutation deficits in spatial learning in a Morris
speech variant of the disease [Zappella of the Mecp2 locus can lead to deficits in water maze task and in conditioned fear,
et al., 2001]. social interaction [Moretti et al., 2005]. and enhanced susceptibility for seizures,
Mouse models of Rett syndrome Interestingly, a recent study has demon- dependent upon maternal transmission
based on a null allele of the Mecp2 strated a link between deficient MECP2 of the mutation [Jiang et al., 1998; Miura
locus demonstrate a phenotype con- expression in human brain or in mouse et al., 2002].
sistent with the human disease. The models, and expression deficits in Mortality early in development is an
mice exhibit normal development until UBE3A and GABRB3, two genes issue for other mouse models relevant
about 5 weeks of age, followed by the linked to Angelman syndrome [Samaco to the ASDs. For example, gestational
emergence of motor impairment, tre- et al., 2005]. death is found with the Nf1-null mouse
mors, hypoactivity, aberrant hind- model for neurofibromatosis type 1
limb clasping, and respiratory symptoms (NF1), an autosomal dominant disorder
characterized by cognitive and language
Mouse Models for Other
deficits, poor motor skills, and tumors of
Disorders Associated
the peripheral nerves [Silva et al., 1997;
Mouse models of Rett syndrome With Autism
North, 2000]. However, behavioral
based on a null allele of the Angelman syndrome is a severe neuro- testing of heterozygotes has revealed that
developmental disorder with clinical Nf1þ/ mice demonstrate deficits in
Mecp2 locus demonstrate a
features of mental retardation, deficits spatial learning in the Morris water
phenotype consistent with the in language, movement disorder, and maze, as well as an enhanced predisposi-
human disease. The mice seizures [Williams, 2005]. The disease tion for tumors [Silva et al., 1997; Costa
has a complex genetic etiology, invol- et al., 2002]. Further, mice carrying a
exhibit normal development ving deletions in chromosome 15q11, an specific allele of Nf1 show deficient
until about 5 weeks of age, area containing the GABAA receptor social transmission of food preference,
beta 3 subunit (GABRB3) gene and impaired fear conditioning and spatial
followed by the emergence of the ubiquitin ligase gene, UBE3A. learning, and retarded acquisition of
motor impairment, tremors, GABRB3 was the first gene mapped to motor performance on a rotarod, but
hypoactivity, aberrant the Prader-Willi/Angelman syndrome without the increased tumor incidence
(PW/AS) region of 15q [Wagstaff et al., [Costa et al., 2001].
hind-limb clasping, and 1991]. Due to imprinting (differential Unfortunately, early mortality has
respiratory symptoms. expression of genes based on parent of precluded behavioral phenotyping of
origin), the phenotype of these deletions some animal models, including the
varies, depending upon which parent model for Smith–Lemli–Opitz/RSH
[Chen et al., 2001; Guy et al., 2001]. transmitted the deletion. Transmission syndrome (SLOS), an autosomal reces-
Female animals heterozygous for the disequilibrium has been demonstrated sive disorder arising from mutations in
targeted disruption have delayed onset of with a marker of GABRB3, as well DHCR7 [Fitzky et al., 1998]. The gene
the phenotype and evidence milder as surrounding markers, in autism encodes an enzyme crucial for choles-
symptoms. A conditional mutation of [Buxbaum et al., 2002]. A targeted terol biosynthesis, suggesting a possible
the locus, where the gene is disrupted disruption of the mouse Gabrb3 locus link between developmental cholesterol
only in the central nervous system, reveals a severe phenotype, with high deprivation and autistic spectrum beha-
shows a similar phenotype to the mortality in neonatal homozygotes viors. The targeted disruption of Dhcr7
Mecp2-null profile [Chen et al., 2001; [Homanics et al., 1997]. The behavioral in mice leads to severe respiratory failure
Guy et al., 2001], indicating that the phenotype of surviving Gabrb3-null and death in newborn homozygotes
protein’s role in the disease process can mice includes seizures, hyperactivity, [Fitzky et al., 2001; Wassif et al., 2001;
be attributed solely to its function in learning and memory deficits, poor see also Yu et al., 2005]. Similarly,
neural tissue, rather than in the periph- motor performance on a rotarod task, the Tsc1-null mouse, a model for
ery. Another allele, Mecp2308, is similar and stereotyped behavior, such as repe- tuberous sclerosis 1, is characterized by
to the truncation allele found in the titive circling [Homanics et al., 1997; an embryonic lethal phenotype [Wilson
human patient population. Mecp2308/Y DeLorey et al., 1998]. Mice heterozy- et al., 2005].44 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMIN. MED. GENET.): DOI 10.1002/ajmg.c ARTICLE
Genes Implicated by Human The HOXA1 locus is located in the
including longer immobility
Genetic Studies of Autism region of human chromosome 7p14.2-
15. A polymorphism changing a histi- in a forced swim task.
Multiple studies in human populations dine residue to an arginine is enriched
have provided evidence that chromo- in patients with ASD over both their
some 7q contains genes conferring unaffected relatives and the rest of [Holmes et al., 2002, 2003; Lira et al.,
susceptibility for autism [e.g., Collabo- the population [Ingram et al., 2000]. 2003]. Enhanced anxiety-like behavior
rative Linkage Study of Autism, 1999]. Hoxa1-null mice show aberrant prenatal is not observed, however, when the null
This region includes several genes development, with delayed hindbrain allele for Sert is placed on a 129S6 strain
important for early brain development, neural tube closure, absent cranial background [Holmes et al., 2003].
including WNT2, Engrailed 2, and nerves, and malformed inner ear struc- Levels of serotonin are partially
HOXA1. WNT2 encodes a secreted tures [Lufkin et al., 1991]. Neither the mediated by monoamine oxidase A
growth factor, which triggers a canoni- En2- nor the Hoxa1-null mice have been (MAOA), an enzyme of the mitochon-
cal signal transduction cascade, utilizing screened for autistic-like behaviors [see drial outer membrane involved in the
the Disheveled 1 (Dvl1) protein. In Murcia et al., 2004]. metabolism of catecholamine and indo-
Drosophila, this signal is required for lamine neurotransmitters. In one study,
expression of the Engrailed locus [Vin- the alleles regulating levels of MAOA
cent and Lawrence, 1994]. The WNT2 were found to correlate with autism
Serotonergic Neurotransmission symptom severity, with the lowest-
locus was suggested to have a role in
autism due to its location within the The strongest evidence for aberrant expressing alleles associated with lower
7q31-3 chromosomal region of interest, neurotransmission in autism involves IQs and more severe autistic behavior
a premise supported by the identification alterations in the serotonergic system, [Cohen et al., 2003]. Mice homozygous
of an autistic patient with a chromoso- with elevated levels of serotonin in blood for the null allele for Maoa have increased
mal breakpoint in the WNT2 gene. reported for up to 45% of autistic serotonin and norepinephrine concen-
Additionally, a single nucleotide poly- patients [Anderson et al., 1990; Cook trations in the brain [Cases et al., 1995].
morphism associated with autism was and Leventhal, 1996]. Clinical trials have Pups exhibit trembling, difficulty right-
found in the locus [IMGSAC, 2001; provided evidence that treatment with ing themselves, and fearfulness, while
Wassink et al., 2001]. A null allele of the fluoxetine, a selective inhibitor of the adults show increased aggression [Cases
mouse Wnt2 locus results in a runting serotonin transporter, can have benefi- et al., 1995]. The MAOA-deficient mice
phenotype, with half of the mutant pups cial effects in the treatment of autism also demonstrate increased freezing in a
dying perinatally due to a placental [Fatemi et al., 1998; Hollander et al., conditioned fear task [Kim et al., 1997],
defect potentially unrelated to autism 2005]. Human genetic studies have hyper-responsivity to acoustic stimuli,
[Monkley et al., 1996]. A mouse model found a link between a short variant of and reduced exploration in a holeboard
with targeted disruption of another the serotonin transporter allele (SERT) test [Popova et al., 2000]. Overall, Sert-
member of the signaling pathway, the and autism [Kim et al., 2002; Conroy and Maoa-null mice demonstrate the
Dvl1-null mouse, shows behavioral and et al., 2004]. significant behavioral effects of altera-
neuropathological defects, including a Mice with targeted disruption of tions in neurotransmission, and are
lack of homecage nesting and social the Sert locus evidence marked decrea- promising candidates for investigation
interaction deficits [Lijam et al., 1997; ses in brain serotonin levels [Bengel et al., of behaviors relevant to the core symp-
Long et al., 2004]. Dvl1-null mice also 1998], as well as decreased aggre- toms of autism.
evidence reduced dendritic arborization ssion, increased anxiety, and increased
[Rosso et al., 2005]. depression-related responses, including
Reeler Mouse
The Engrailed 2 locus on human longer immobility in a forced swim task
chromosome 7q36 has been implicated The RELN locus encodes a large protein
in ASD by an association study [Gharani that acts as a serine protease of the
et al., 2004]. A targeted disruption of the Mice with targeted extracellular matrix [Fatemi, 2005]. The
mouse homolog was generated prior to locus was originally identified as a
the link with ASD. Homozygotes are
disruption of the Sert spontaneous mouse mutation, Reeler.
viable and fertile, but have abnormal locus evidence marked Reeler animals showed impaired motor
foliation of the cerebellum [Joyner et al., decreases in brain coordination, tremors and ataxia
1991]. Further studies utilizing the En2 [Falconer, 1951]. The gene was subse-
mutant mouse have suggested a role for serotonin levels, as well as quently identified and the Reeler allele
the gene in regulating development of decreased aggression, increased shown to be a deletion of about 150 kb,
serotonergic, noradrenergic, and dopa- generating a null allele. Examination of
minergic neurons [Alberi et al., 2004;
anxiety, and increased Reeler brains revealed that neurons failed
Simon et al., 2005]. depression-related responses, to migrate to the correct location,ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMIN. MED. GENET.): DOI 10.1002/ajmg.c 45
resulting in disorganization of lamina- criteria. Therefore, validity of mouse tained in one side chamber of the test
ted regions, such as the cerebellar and models for this disorder is dependent box, or remaining alone in the center or
cerebral cortices. Studies have reported upon reflection of core behavioral opposite side chambers. The unfamiliar
that specific human polymorphisms in symptoms, including impairments in stranger mouse is enclosed in a small
the RELN locus can be associated with social interaction and deficiencies in wire cage, which allows visual, auditory,
autism susceptibility [Persico et al., other functional domains. While the olfactory, and some tactile contact, but
2001; Skaar et al., 2004], although this use of a behavioral testing screen with precludes aggressive or sexual interac-
association is not observed in all autism measures relevant to the clinical syn- tions. An identical wire cage is placed in
patient populations [Bonora et al., drome is crucial for the development and the opposite side chamber to control for
2003]. evaluation of appropriate animal models the effects of object novelty. Measures
Due to overt neuroanatomical [Rodier, 1996; Insel, 2001; Murcia et al., are taken of the amount of time spent in
pathology, the Reeler mouse has been 2004], few mouse tests have been and entries into each side of the test
extensively investigated as an animal targeted toward the constellation of box, as well as time spent sniffing the
model for brain dysfunction. In addition symptoms characteristic of the ASDs. wire cages. Initial work with this test
to the association with autism, changes Our research group at the University of for social approach has shown that
in RELN have also been linked with North Carolina, in consultation with most, but not all, of selected inbred
many neuropsychiatric disorders, inclu- clinicians, therapists, and other profes- mouse strains choose to spend more time
ding schizophrenia, bipolar disorder, and sionals working in the field of autism, has near the unfamiliar stranger. This pre-
depression, as well as with lissencephaly designed a set of mouse behavioral tasks ference for social proximity can be
[Fatemi, 2001], suggesting that the Reeler to model specific aspects of autistic-like observed in juvenile and adult mice,
mouse does not provide a model for behavior, such as tendencies for social and in males and females [Brodkin et al.,
brain alterations specific to autism. Apart avoidance [Moy et al., 2004; Nadler 2004; Moy et al., 2004; Nadler et al.,
from the overt motoric deficits, Reln et al., 2004], repetitive responses, and 2004].
mutant mice show increased anxiety and resistance to change. The testing screen The second phase of the test assesses
stereotypy in an open field, increased is composed of assays for sociability, preference for social novelty. In this case,
social dominance in a tube test, and preference for social novelty, and learn- the mice are given a choice between
learning deficits in the Morris water ing acquisition and reversal, as well as the unfamiliar mouse from the first phase
maze task [Salinger et al., 2003; Lalonde control measures for motor and sensory (stranger 1), and a new unfamiliar mouse
et al., 2004]. Some studies have reported function, including olfaction. Table II (stranger 2) placed in a wire cage in
behavioral abnormalities in heterozy- presents a summary of mouse behavioral the opposite side of the test box. We have
gous Reeler mice, which have levels of tasks that may be relevant to elements of observed that most, but not all, of the
RELN protein in brain reduced by the autism phenotype. inbred mouse strains we have tested
approximately 50% [Tuetling et al., demonstrate a shift in preference, so that
1999]. Aberrant responses observed more time is spent with the novel
Measures of Social Behavior
in Relnþ/ mice included increased stranger 2, rather than the more-familiar
anxiety, deficits in prepulse inhibition Given that impairments in social inter- stranger 1. This phase of the social
of acoustic startle, and learning delays action and communication are the preference test provides information on
in an olfactory discrimination task primary diagnostic indicators in ASDs the ability of the mice to distinguish
[Tuetling et al., 1999; Larson et al., [American Psychiatric Association, between two unfamiliar conspecifics.
2003]. Heterozygous Reeler mice were 1994], we considered the assessment of The social preference tests allow the
also found to have decreased dendritic social behavior as an essential compo- assessment of both social approach and
spine density [Liu et al., 2001] and nent for our behavioral testing battery. avoidance, using a relatively rapid, auto-
reduced levels of oxytocin receptors in The first measure involves simple obser- mated task [Nadler et al., 2004]. Further
brain [Liu et al., 2005]. However, other vations of nest-building and huddling in characterization of social behavior can
studies have failed to find differences the home cage, which can provide early utilize observations of social interaction
between Relnþ/ mice and normal indications of aberrant social behavior in an open field or neutral cage, the
controls, suggesting the lack of a clear [Lijam et al., 1997; Mohn et al., 1999; resident-intruder paradigm, or tube tests
gene-dosage relationship [Salinger et al., Moretti et al., 2005]. For a more quan- for social dominance [Mineur et al.,
2003]. titative evaluation of social approach and 2002; Duncan et al., 2004; Long et al.,
avoidance, we conduct a social investi- 2004; Spencer et al., 2005]. Measure-
gation task in a three-chambered appa- ment of ultrasonic vocalizations in
MOUSE BEHAVIORAL
ratus [Moy et al., 2004; Nadler et al., mouse pups removed from the nesting
MEASURES RELEVANT TO
2004; see also Brodkin et al., 2004]. In area can provide information on respon-
THE AUTISM PHENOTYPE
the first phase of this test, mice are given ses to social isolation early in develop-
The diagnosis of autism is based on a choice between spending time in the ment [Holtzman et al., 1996; Moles
behavioral, rather than physiological, proximity of an unfamiliar mouse, con- et al., 2004].46 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMIN. MED. GENET.): DOI 10.1002/ajmg.c ARTICLE
TABLE II. Mouse Behavioral Tasks for Modeling the Autism Phenotype
Symptom in autism Mouse behavioral task References
Social interaction deficits Home cage observation Lijam et al. [1997]; Moretti et al. [2005]
Social approach tests Moy et al. [2004]; Nadler et al. [2004]
Resident-intruder interaction Mohn et al. [1999]; Moretti et al. [2005]
First symptoms early in development, Ultrasonic vocalization in pups Holtzman et al. [1996]; Moles et al. [2004]
communication deficits
Restricted interests, repetitive behavior; Home cage observation Wu and Melton [1993]; Presti et al. [2003]
stereotypies, self-injury Behavior in an open field DeLorey et al. [1998]; Turner et al. [2001]
Nose-poke, hole board test Popova et al. [2000]; Bell et al. [2003]
Novel object test Salinger et al. [2003]; Yan et al. [2004]
Resistance to change Reversal learning Bakker et al. [1994]; Kooy et al. [1996]
Anxiety Elevated plus maze Griebel et al. [2000]; Ren-Patterson et al. [2005]
Light-dark transition test Bouwknecht and Paylor [2002]; Peier et al. [2000]
Changes in sensory reactivity Prepulse inhibition of startle responses Tuetling et al. [1999]; Nielson et al. [2002]
Hot plate analgesia test Martinez-Cue et al. [1999]; Long et al. [2004]
Motor deficits, clumsiness Balance beam, climbing pole tests Lalonde et al. [2004]; Moretti et al. [2005]
Rotarod performance Gerlai et al. [1996]; Miura et al. [2002]
Mental retardation Morris water maze, hidden platform task Sago et al. [1998]; Lalonde et al. [2004]
Radial arm maze Mineur et al. [2002]; Yan et al. [2004]
Operant conditioning Driscoll et al. [2004]; Frankland et al. [2004]
Passive avoidance DeLorey et al. [1998]; Lira et al. [2003]
Conditioned fear Kim et al. [1997]; Costa et al. [2001]
Measures for Repetitive Behavior the task is measured by removal of the forcement is switched, so that mice must
and Restricted Interests escape platform before a final probe trial. now choose the opposite arm to earn
Normal animals will swim to and circle rewards. One disadvantage of this task is
In mice, repetitive behavior can include over the area where the platform had that mice must be food-deprived before
perseverative sniffing, circling, digging, been located. In the next phase of acquisition, which can lead to issues
or continuous cage-running and jump- testing, the escape platform is placed in of motivational levels across strains.
ing [Cases et al., 1995; Homanics et al., a different region of the pool, and mice Another procedure using the T-maze is
1997; Presti et al., 2003]. Repetitive are re-assessed on learning the new the spontaneous alternation test, which
grooming and scratching can lead to self- location. Delayed or deficient acquisi- relies on the nature tendency of mice to
injury, such as torn ears and skin lesions tion during reversal learning could serve alternate arm choices in a maze. Mice
[Wu and Melton, 1993]. Aberrant as a model for autistic-like cognitive with the Relnrl-orl mutation demonstrate
stereotypies can be noted during rigidity. In line with this premise, perseverative responses in this test
home-cage observations or during Fmr1-null mice show normal acquisi- [Lalonde et al., 2004].
open-field testing. tion of spatial learning in the Morris Other ways to assess repetitive beha-
The predisposition for repetitive water maze task, but impaired learning vior include measures of exploration on a
behavior in autism can also be seen during the reversal phase [Bakker et al., hole-board, with counts taken of nose-
in an excessive adherence to routine. 1994; Kooy et al., 1996]. pokes into a restricted set of holes, versus
Reversal learning in the Morris water Mice with visual or motor impair- the entire board [Popova et al., 2000;
maze task can be used as a measure of ments may not be able to perform in Bell et al., 2003], and the investigation of
resistance to change a learned pattern of the water maze test. In these cases, a novel objects in an open field [Salinger
behavior. In this task, mice are trained to simple T-maze task can be used to et al., 2003; Yan et al., 2004].
locate a hidden escape platform, which is evaluate learning acquisition and rever-
slightly submerged in a circular pool of sal. Mice are trained to enter one
Interpretation of Results From
opaque water. Over several days, mice particular arm (left or right) of the maze
Behavioral Tests
learn to swim directly to the escape to obtain a food reward. When a high
platform from any release point in the rate of correct choices has been While deficits in social interaction and
periphery of the pool. Spatial learning in observed, the arm designated for rein- aberrant repetitive behavior may be keyARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMIN. MED. GENET.): DOI 10.1002/ajmg.c 47
features of the autism behavioral phe- mutation, a higher rate of inactivation ches which can address the genetics of
notype, the human disorder is character- for the mutation-bearing chromosome these diverse pathways to achieve a more
ized by the variable inclusion of many can result in a less severe phenotype. global view of the etiology of autism.
other symptoms [e.g., Muris et al., However, the effect of X inactivation Discovering genes important for normal
1998]. Table II lists several functional can be controlled in Mecp2-mutant social behavior in mice could lead to
domains of behavior, including anxiety, mice by only using males as subjects the identification of brain mechanisms
sensory reactivity, motor skills, and [Shahbazian et al., 2002]. In Angelman that play a role in the impaired inter-
cognitive abilities, that may or may not syndrome, symptoms are dependent on action and communication characteriz-
be changed in mouse models for ASDs. whether the chromosome bearing the ing ASDs. Gene expression profiles for
In addition, the behavioral battery mutation was inherited from the father mouse models characterized by aberrant
utilized by our laboratory includes con- or the mother [for review, see Williams, social behavior, such as oxytocin or
trol measures, such as tests for activity 2005]. Parent of origin imprinting vasopressin deficient mice [Insel et al.,
level and olfactory ability, that can be causes expression of a subset of genes 1999; Lim et al., 2005], 5-HT1A- and
crucial for the interpretation of observed from only one of two copies, maternal 1B- knockouts [Zhuang et al., 1999;
deficits in social preference [Moy et al., and paternal, present in the genome. see also Gingrich and Hen, 2001],
2004], as well as other tasks relevant to The effect of imprinting can be con- dopamine transporter knockout mice
autism. trolled in mouse models by setting up [Rodriguiz et al., 2004], or mice with
crosses that transmit the mutation from reduced levels of NMDA receptors in
the appropriate parent [e.g., Jiang et al., brain [Mohn et al., 1999; Duncan et al.,
DISCUSSION
1998; Miura et al., 2002; Liljelund et al., 2004] could suggest new genetic targets
The complex interaction of genes that 2005]. for studies in human populations. Beha-
appears to underlie susceptibility for the Possible interactions between the vioral tasks relevant to the autism
autism phenotype is problematic for disease mutation and the genetic back- phenotype could also be revealing in
development of animal models of the ground of the mouse model should also the case of mouse models which reflect
ASDs. Many of the mouse models be considered. Susceptibility for the neuropathology relevant to autism,
described in this review involve targeted effects of the targeted locus may differ including changes in cerebellum [e.g.,
disruption of a candidate gene. One across background strains, as observed in the Engrailed mouse, Joyner et al., 1991;
disadvantage of this approach is that the Fmr1-null mouse [Dobkin et al., 2000], see also Murcia et al., 2004] or brain
complete removal of a protein in brain Sert-null mice [Holmes et al., 2003], overgrowth [e.g., IGF-overexpressing
can lead to severe impairments or early and Tsc1 heterozygotes [Wilson et al., mice, Hodge et al., 2005]. Thorough
mortality, as observed with mouse 2005]. Mouse geneticists should also behavioral phenotyping provides an
models for Angelman and Smith– consider strain characteristics when gen- advantageous first approach to deter-
Lemli–Optiz syndromes [Homanics erating mouse models. For example, the mine which mouse models for ASDs
et al., 1997; Fitzky et al., 2001]. In 129SvEv inbred mouse strain, a line would offer the most valuable candidates
addition, the null allele might not widely used in laboratory research, is for detailed genetic characterization.
properly recapitulate the disease pheno- characterized by reduction or loss of the
type in the animal model. In the case of corpus callosum and, in some cases, poor
ASDs, many of the alleles identified in performance in learning tasks [Balogh
candidate genes are not null alleles. et al., 1999; Wahlsten et al., 2001]. Thorough behavioral
Rather than a complete loss of function, In addition, several inbred mouse
phenotyping provides an
autism-susceptibility alleles may cause strains, including FVB/NJ, C3H/HeJ,
alterations in the structure of the result- and SJL/J, carry the gene for retinal advantageous first approach to
ing proteins, affect the amount of protein degeneration, with blindness occurring determine which mouse models
produced, or protein stability within the by weaning age [The Jackson Labora-
cell. tory, 2002]. Intrinsic alterations in brain for ASDs would offer the most
Other biological processes contri- morphology, sensory function, and valuable candidates for detailed
bute to the variability seen in disease learning ability are confounding factors
phenotype. Some genetic complexity, in the use of these strains to model
genetic characterization.
such as X-inactivation or parent-of- autistic-like behaviors.
origin imprinting, can be controlled The genes involved in the regula-
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