Fmr1 KO Mice as a Possible Model of Autistic Features

Abstract

Autism is a pervasive developmental disorder appearing before the age of 3, where communication and social interactions are impaired. It also entails stereotypic behavior or restricted interests. Although this disorder was first described in 1943, little is still known about its etiology and that of related developmental disorders. Work with human patients has provided many data on neuropathological and cognitive symptoms, but our understanding of the functional defects at the cellular level and how they come about remains sketchy. To improve this situation, autism research is in need of valid animal models. However, despite a strong hereditary component, attempts to identify genes have generally failed, suggesting that many different genes are involved. As a high proportion of patients suffering from the Fragile X Syndrome show many autistic symptoms, a mouse model of this disorder could potentially also serve as a model for autism. The Fmr1 KO mouse is a valid model of the Fragile X Syndrome and many data on behavioral and sensory-motor characteristics of this model have been gathered. We present here an assessment of autistic features in this candidate model. We conclude that Fmr1 KO mice display several autistic-like features, but more work is needed to validate this model.

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Mini-Review Article
TheScientificWorldJOURNAL (2006) 6, 1164–1176
ISSN 1537-744X; DOI 10.1100/tsw.2006.220
*Corresponding author.
©2006 with author.
Published by TheScientificWorld, Ltd.; www.thescientificworld.com
1164
Fmr1 KO Mice as a Possible Model of
Autistic Features
Maude Bernardet* and Wim E. Crusio
Laboratoire de Neurosciences Cognitives, CNRS UMR 5106, Université de
Bordeaux I, Bat B2 - Avenue des Facultés, 33405 Talence Cedex, France
E-mail: m.bernardet@lnc.u-bordeaux1.fr
Received June 26, 2006; Revised September 1, 2006; Accepted September 6, 2006; Published September 20,2006
Autism is a pervasive developmental disorder appearing before the age of 3, where
communication and social interactions are impaired. It also entails stereotypic behavior
or restricted interests. Although this disorder was first described in 1943, little is still
known about its etiology and that of related developmental disorders. Work with human
patients has provided many data on neuropathological and cognitive symptoms, but our
understanding of the functional defects at the cellular level and how they come about
remains sketchy. To improve this situation, autism research is in need of valid animal
models. However, despite a strong hereditary component, attempts to identify genes
have generally failed, suggesting that many different genes are involved. As a high
proportion of patients suffering from the Fragile X Syndrome show many autistic
symptoms, a mouse model of this disorder could potentially also serve as a model for
autism. The Fmr1 KO mouse is a valid model of the Fragile X Syndrome and many data
on behavioral and sensory-motor characteristics of this model have been gathered. We
present here an assessment of autistic features in this candidate model. We conclude
that Fmr1 KO mice display several autistic-like features, but more work is needed to
validate this model.
KEYWORDS: animal model, autism, autistic-like traits, behavior, Fmr1 KO mice
AN OVERVIEW OF AUTISM
Autism is classified as a developmental pervasive disorder, the diagnosis of which is based on behavioral
symptoms and age of onset[1], with the earliest manifestations appearing before the age of 3. Essential
behavioral features of autistic disorder fall into three classes: abnormal or altered social interactions,
abnormal or altered social communication, and a restrained repertory of interests and activities.
Symptoms vary greatly between individuals[2,3,4]. Due to the variable clinical picture and the
accompanying blurring of diagnostic classes, estimations of the prevalence of autism vary widely, but
cluster around 6 births per 1000[5,6,7,8,9,10]. The syndrome is much more frequent in boys than girls,
with a ratio around 4:1.
Altered nonverbal social and communicative behaviors concern social gaze, facial mimics, body
postures, and gestures[1,3]. Autistic individuals often fail to establish relations with peers corresponding
to their levels of development. They may not spontaneously share their interests, pleasures, or

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achievements with other people, and may lack social or emotional reciprocity[3,11,12]. Qualitative
communication alterations include a late display or complete lack of spoken language development
without compensation by nonverbal communication[1]. Even in subjects who master language
sufficiently, an inability to engage or sustain a conversation with a peer can be observed. Stereotyped and
repetitive use of language or idiosyncratic speech may occur. Lack of spontaneous playacting and of
social imitation play according to age of development also occurs frequently. The restrictive, repetitive,
and stereotyped character of behaviors, interests, and activities may be manifested by a preoccupation
circumscribed to one or more interest centers that is abnormal in its intensity or in its orientation. This
may also show as inflexible adhesion to habits, unspecific and nonfunctional rituals, or by stereotyped
motor mannerisms or persistent preoccupation for objects or parts of the body[3,13].
The core features of autism described above, defining the diagnosis of this disorder, are also
frequently associated with variable accompanying symptoms[1]. In most cases, mental retardation occurs,
the severity of which varies from light to profound (see [14] for a discussion). The profile of cognitive
capacities is usually heterogeneous and some particular skills may occur at a much higher level than most
other skills. Individuals with autism can display a variety of behavioral traits, such as hyperactivity,
attention deficit[15], impulsivity, self-injurious behavior, and, particularly in the youngest, anger
crises[16]. Mood or affect perturbations are frequent[17], as are disturbed sleep patterns[18,19]. The child
can lack fear in some dangerous situations, but show excessive fear in others. Responses to sensory
stimuli can be abnormal, e.g., a high threshold to pain, and hypersensitivity to noise and physical contact,
overreaction to lights or odors, or fascination for certain stimuli[20]. Convulsions occur in 5–38% of
cases, particularly before 5 years of age or in teenagers[21].
THE PUZZLE OF AUTISM: WHAT WE KNOW AND HOW WE KNOW IT
Since its description in 1943 by Kanner[3], there have been many efforts to link the behavioral features of
autism to underlying neural abnormalities. Psychiatric observations, combined with data from
experimental psychology, autopsies, and anatomic and functional magnetic resonance imaging, have
started to shed some light on the nature of this affliction. The anomalies observed in different brain
structures have led to different hypotheses implicating dysfunctions of the amygdala[11], orbitofrontal-
amygdala circuit[22], frontal-striatal system, and cerebellum[23]. In addition, alterations in various
neurotransmitter systems have been postulated[2].
Many structures were found to have an altered cytoarchitecture in autistic patients' brains: corpus
callosum[24,25,26], parts of the limbic system, cortex[27,28], cerebellum, and brainstem, but
observations were not always replicated. In the limbic system, the hippocampus, amygdala, entorhinal
cortex, subiculum, mammillary body, anterior cingulate cortex, and septum display small cell sizes and
increased cell packing densities at all ages (reviewed in [29,30]). Golgi analysis of CA1 and CA4
pyramidal neurons has shown decreased complexity and extent of dendritic arbors in these cells[31]. The
cerebellum is also affected. Decreases in numbers of Purkinje cells were systematically observed,
particularly in the inferior posterior hemisphere regions of the cerebellum[27,32,33,34].
Alterations may also differ as a function of age. Studies suggest that neurons in the vertical limb of
the diagonal band of Broca, in cerebellar nuclei, and in the inferior olive are abnormally large and
numerous in young individuals with autism, but are small, pale, and significantly reduced in number in
adult autistic individuals[27,29,30]. The events resulting in the observed decreased numbers of Purkinje
cells may occur before the connections between fibers of the olivary neurons and the Purkinje cells are
formed, and may account for a possible prenatal cause of autism (see [30]).
It was found that brains of children with autism are larger than those of age-matched controls, while
the brains of autistic adults tend to be lighter than controls[35]. Brain enlargement seems to be postnatal
as newborns show few or no differences with controls[36]. Many mechanisms have been hypothesized to
explain these observations, such as increase in neurogenesis, decrease in neuronal apoptosis, increase in
glial cell production, diminished synaptic pruning, or myelin abnormalities, but none has been confirmed.

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It has been proposed that autistic disorders may have viral[37], autoimmune[38], teratogenic[39], or
genetic origins[40,41], none of these hypotheses being exclusive of the others. Congenital and neonatal
TORCH infections (acronym for Toxoplasmosis, Others [syphilis, varicella-zoster, and parvovirus B19],
Rubella, Cytomegalovirus, and Herpes) or autoimmune reactions to these pathogens have been associated
with autism[42,43]. Drug use during pregnancy has also been linked to increased frequency of autism. For
example, anticonvulsants, the mood stabilizer valproic acid, and antiemetic thalidomide have teratogenic
effects during early stages of intrauterine development. Minor malformations that occur frequently in
people with autism are known to arise in the same stages[39].
Support for a genetic basis of autism comes from a variety of sources, such as epidemiologic surveys,
family and twin studies, and linkage analyses[41,44,45]. Gross disruptions of chromosomal material
account for about 5% of cases of autism[46,47,48] and 5–12% of cases arise from disorders that affect the
brain and have a known genetic etiology, such as tuberous sclerosis and neurofibromatosis[49,50].
Samples of the remaining cases of idiopathic autism have been examined for heritability in family and
twin studies. Around 5% of siblings of autistic individuals will also develop the disorder; a rate that is 50
times higher than the 0.1% prevalence of autism in the general population[6,51]. In addition, 60–90% of
monozygotic twins are concordant for this disorder[52,53,54] and many family members of probands
appear to present various autistic traits, but in a milder form[55]. Genetic linkage studies have been
conducted on autistic probands and their families. Numerous loci have been found to be potentially linked
to the disorder, most of them being more or less specific for a given population[44]. Candidate genes
include alleles of genes implicated in development, e.g., Reelin and engrailed2, and others, such as the
SERT gene (serotonin transporter; [56,57]).
In conclusion, studies on humans have increased our understanding of autism and its developmental
origin is now generally accepted. Nevertheless, we still lack specific hypotheses to explain not only
autistic symptoms, but also their heterogeneity and their emergence during development. Human studies
are limited due to the scarcity of study material, personal and uncontrollable history of individuals,
variability and uncontrollability of genetic background, inability to isolate genetic and environmental
factors, indirect inference of brain operation within the limitations of current noninvasive methods to
investigate the brain, and the difficulty with which experimental results replicate. A valid animal model,
therefore, could clearly help to advance our knowledge significantly. A major challenge of any model of
autistic brain development is to take into account the neural substrates implicated and the variations that
can be observed between affected individuals.
FURTHER UNDERSTANDING: LOOKING FOR ANIMAL MODELS
It will be evident that no exact mouse equivalent can exist for such exquisitely human traits as are
affected in autism, or for any of the other common psychiatric disorders, for that matter. Moreover, some
human brain structures hardly have an equivalent or develop differently in mice. The prefrontal cortex,
for example, is thought to be involved in cognitive rigidity and is poorly developed in mice[58]. In order
to be useful, however, an animal model does not need to recapitulate a human disorder or syndrome
exactly. Indeed, it would appear that several of the intermediate traits (or endophenotypes) of autism can
be modeled in animals[59,60].
For an animal model to be considered relevant in psychiatric research, it should meet different criteria
of validity, such as construct, face, and predictive validity[61,62,63]. Thus, an acceptable animal model
for autism should reflect the developmental problems discussed above to satisfy the criterion of construct
validity. Face validity means that the model should display autistic-like behavioral traits resembling core
symptoms of autism concerning social relations, social communication, and restricted activities, and
should at least approximate most of the variable symptoms, such as anxiety, mental retardation,
clumsiness, aggression, hyperactivity, abnormal sensory responses, and stereotypies. Several behavioral
tasks have been designed for mice to assess autistic-like traits[64]. If indeed present, such behavioral
traits could be studied in the model after challenge with possible medications used in autistic patients to

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improve particular symptoms. Predictive validity of the model would be established when these drugs
reduce or improve symptoms not only in the model, but in human patients, too.
Primates have been used to study social relations and social communication, but they have limitations
because of their high financial cost, long developmental time span, the fact that genetic manipulation is
impractical, and ethical considerations. Rodents do not suffer from these drawbacks. A limitation to the
use of rodent models for autism is the difficulty to model specific human features such as social gaze and
sharing of interests. Nevertheless, as we will see below, most behavioral features of autism can be
modeled in mice, which therefore could render valuable models for autism.
Belzung et al.[58] classified models for autism in four categories: (1) animals mutated for
neuropeptides implicated in social behavior and attachment (vasopressin, oxytocin, µ-opioid receptors),
(2) models of epigenetic factors implied in autism (developmental deficits in serotonin, fetal exposition to
anticonvulsants or thalidomide), (3) neonatal lesions of autism-associated structures, and (4) models of
genetic diseases associated with autism (e.g., Fragile X or Rett Syndrome and others). The problem with
the majority of these models is that they concern only some aspects of the etiology and not the whole
symptomatology, although the functional role of several structures has become better understood with
their help. Moreover, most of these models have up till now only been tested for a few autistic-like traits.
In what follows, we will review evidence that one of the models of Belzung's fourth category, the Fmr1
KO mouse, might also serve as a model for autism.
THE FRAGILE X SYNDROME
The FMR1 mutation underlying the Fragile X syndrome (FXS) is the most frequent cause of inherited
mental retardation and is interesting here because about 10–30% of these patients are also diagnosed with
autism[49,65,66,67]. FXS accounts for around 5% of the autistic population[49,68,69]. Many autistic
behavioral traits are common in FXS, even in patients that are not formally diagnosed with autism. FXS
also shares many of the variable features of autism such as hyperactivity[70], stereotypical behavior,
aggressiveness, anxiety (particularly due to social stress[70]), disturbed sleep patterns[71], high
prevalence of epilepsy[72], and impairment in sensorimotor gating[73]. Both disorders are developmental
and affect more boys than girls. It is interesting to note that although due to a single mutation, FXS
symptoms are very variable in quality and severity between individuals, another parallel with autism. For
all these reasons, autism researchers have become increasingly interested in FXS[74].
The FMRP protein, the product of the FMR1 gene, is expressed in brain tissue and in testes. In
neurons, it is localized either in the nucleus or cytoplasm[75,76,77], depending on the splicing[75]. It
complexes with other proteins[78] and is implicated in mRNA transport and translation
regulation[78,79,80,81]. Its own translation is thought to be dependent on synaptic activity. Although
much is known about its conformation, expression pattern, and localization, its role in mental retardation
remains to be elucidated.
A knock-out mutation has been induced in the mouse Fmr1 gene, which is 98% similar to its human
ortholog, FMR1[82]. FMRP expression was disrupted by introducing a neomycin cassette into exon 5 of
the gene[82]. Recently, Yan et al.[83] observed some residual Fmr1 RNA expression in these animals that
may be due to alternative splice variants. Nevertheless, Fmr1 KO mice display macroorchidism and
cognitive and other behavioral deficits comparable to those of human FXS patients[82]. In addition, the
abnormally long and thin dendritic spines characteristic of FXS patients are also found in young
KOs[84,85,86,87,88]. Fmr1 KO mice have been tested for numerous behavioral tasks relevant to FXS
and these animals have therefore been validated as a model for this disorder[89]. The relatively lighter
symptomatology of the disorder that has been observed in these mice for some features may be due to the
above-mentioned residual expression of splice variants of Fmr1 RNA[83].
The Fmr1 KO was produced in a 129 ES cell line and the resulting mutants were then recurrently
backcrossed to both C57BL/6J (B6) and FVB/N (FVB) animals. It appears that the mutation expresses
differently on these two backgrounds[90,91].

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Fmr1 KO MICE: BEHAVIORAL CHECKUP RELEVANT TO AUTISTIC TRAITS
Fmr1 KO mice have been extensively studied for a large variety of behavioral and sensorimotor traits (see
Tables 1 and 2). Most studies aimed to validate these mice as a model for FXS and thus only relatively
few studies have assessed behavior relevant to the core symptoms of autism. An exception is abnormal
social behavior, which is also a prominent feature of FXS.
TABLE 1
Phenotypical Checkup of Fmr1 KO Mice: Behaviors Relevant to Core Symptoms of Autism
Test Background Result Ref.
Inappropriate social interactions
Mirrored chamber test B6 KO < WT for % time in the mirrored chamber [94]
Tube test of social dominance B6 KO < WT vs. unfamiliar WT the first time
KO = WT vs. unfamiliar WT the third day
KO = WT vs. familiar WT
[94]
Social interaction test B6 KO vs. WT:
Active social behavior: KO > WT
Passive social behavior: KO < WT
KO vs. KO, WT vs. WT:
Sniffing and receptive behavior: KO > WT
KO vs. C3H, WT vs. C3H: KO < WT
[94]
[95]
Crawley test B6 KO = WT [94]
Influence of cage familiarity on
response to unfamiliar social
partners
B6 In an unfamiliar cage: KO = WT; in a familiar
cage: KO < WT during the first 5 min, KO >
WT after 20 min
[94]
Perseverance
Water maze reversal learning:
Hidden-platform condition
Visible-platform condition
B6
B6
B6
B6
B6
B6
KO = WT
Escape latencies: KO > WT
Path length: KO > WT
Number of trials: KO > WT
Rate of learning:
KO = WT,
KO>WT
Escape latencies:
KO > WT
KO = WT
[97,98]
[82,89,96]
[96]
[98]
[96]
[89]
[96]
[82]
E-shaped water maze reversal
learning
B6 KO = WT [89]
Plus-shaped water maze
reversal learning
B6 Escape latencies: KO = WT, but rate of
learning: KO < WT
[98]
Although some core symptoms, such as sharing pleasures and interests with others, can hardly be
modeled in rodents, the inability to establish normal relations with peers and the lack of social reciprocity
can be assessed more easily. The mirrored chamber test, for instance, was developed by Seale and his
team[92] based on the notion that most animals react to their mirror image as if it was another animal[93].
The apparatus consists of a box, the interior of which is totally mirrored, laid out in the center of a dark
open field; the wall opposite the chamber is also mirrored. Fmr1 KO mice were found to spend less time
in the center mirrored chamber compared to total time spent in the mirrored alley (considered to be less
anxiogenic) and the mirrored chamber[94]. A tube test can be used to evaluate social dominance. If two

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TABLE 2
Phenotypical Checkup of Fmr1 KO Mice: Behaviors Relevant to Variable Symptoms of Autism
Test Background Result Ref.
Anxiety
Elevated plus maze FVB
B6
FVBxB6
KO = WT
KO = WT
KO = WT
[100]
[91,107]
[107]
FVBxB6 KO less anxious than WT [83]
Thigmotaxis in open-field B6
FVBxB6
KO < WT
KO < WT
[94,101]
[83]
Boli in open-field
Light-dark exploration
B6
B6
KO < WT
Transitions between compartments: KO > WT
Time spent in both compartments: KO = WT
[94]
[82,101]
Corticosterone response to
acute stress
B6 Males:
Sham and 15 min: KO = WT
0 min: KO < WT
60 min: KO > WT
Females:
Sham, 0 and 60 min: KO = WT
15 min: KO < WT
[104]
B6 Males:
No stress, 30 min stress: KO = WT
2 h stress: KO > WT
[103]
Conditioned emotional response B6 KO = WT [98]
Learning and memory
Cross-shaped water maze
FVB
B6
Correct trials: KO < WT
Escape latencies: KO = WT
Correct trials:
KO < WT
KO = WT
[102]
[98]
[98]
[102]
Changing position of platform in
water maze
B6 KO = WT [97,98]
E-shaped water maze B6 KO = WT [89]
Morris water maze training:
Hidden-platform condition
Visible-platform condition
B6
FVBxB6
B6
FVB
B6
Escape latencies:
KO = WT
KO > WT
KO > WT the first four trials
Escape latencies: KO > WT
Rate of learning: KO = WT
Rate of learning: KO < WT
Escape latencies: KO = WT
[96,97,101]
[89]
[82]
[83]
[82,89,102]
[102]
[82,96]
Radial maze B6 Working memory: KO = WT [91]
FVBxB6 Working memory: KO < WT the first 6 days;
reference memory: KO < WT; strong choice
design: KO = WT
[83]
Barnes maze FVBxB6 KO = WT; during probe test: KO < WT [83]
Fear conditioning: context and
conditioned cue
FVB
B6
B6
KO = WT
KO = WT
KO < WT
[102]
[98,101,102]
[97]
Trace fear conditioning B6 KO < WT [100]
Conditioned eyelid blink reflex B6 KO < WT [109]

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TABLE 2 (continued)
Test Background Result Ref.
Learning and memory (continued)
Passive avoidance (latency to
enter dark compartment)
B6
FVB
KO = WT
KO = WT
[82]
[108]
Lever press escape/avoidance
task
B6 KO < WT [113]
Instrumental conditioning B6 Conditioning learning : KO = WT [73]
Devaluation of reward and omission of lever
press : KO > WT
Olfactory learning and memory
tasks
FVBxB6 KO = WT [83]
Novel object task FVBxB6
FVB
KO = WT
KO < WT
[83]
[114]
Motor abilities
Rotarod motor coordination and
balance
B6 KO = WT [101]
Aggression
Neutral cage aggression test B6 KO = WT [91]
Hyperactivity
Open field activity B6
B6
FVBxB6
FVB
FVB
KO > WT
KO = WT
KO = WT
KO = WT
KO = WT before 18 min
KO > WT after 18 min
[91,94,101]
[107]
[107]
[100]
[108]
Activity cage FVB KO > WT [114]
Motor activity test B6 KO > WT [82]
Idiosyncratic responses to sensory stimuli
Auditory startle response B6 KO = WT, but increased response with
Fmr1gene containing YAC
[101]
B6 KO > WT at 70 and 80 dB; KO < WT at 120 dB [107]
B6 KO < WT at higher intensities, interaction
between genotype and intensity
[73]
FVB KO < WT [110]
FVB KO = WT under 110 dB; KO< WT from 110 dB
and above
[108]
FVBxB6 KO > WT at 80 dB; KO < WT at 100, 110, and
120 dB
[83]
FVBxB6 KO = WT [83]
Prepulse inhibition B6 KO > WT [73]
B6 KO > WT at 67 dB (2 dB above background
noise)
[107]
FVB KO > WT [110]
Audiogenic seizures (AS) FVB
B6 and FVBxB6
KO after long loud sound and after age 10 weeks
KO >> WT (143 ± 5 days)
KO >> WT (45 days and under)
KO display AS, WT do not (21 days)
[110]
[115]
[108]
[83]
FVB KO >> WT (30 days) [83]
Hot plate and tail-flick test FVB KO = WT [100]

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mice enter a tube at opposite sides, meeting in the center, generally, one will push back the other and
hence be called dominant. The number of matches won by KO mice appeared to be dependent on the
familiarity of the opponent animal. Familiarity of the environment also has an effect on social
interactions; KO and WT spent as much time at the interface of two compartments with an unfamiliar
mouse in an unfamiliar cage, but they displayed a different pattern of social exploration when put in a
familiar cage[94].
Social interaction tests conducted by Spencer et al.[94] revealed that KO mice showed increased
active social behaviors when confronted with a WT or KO animal, increased receptive social behaviors
when opposed to a WT, and decreased receptive social behaviors when confronted with KO peers. In the
social interaction test conducted by Mineur et al.[95] using C3H ovariectomized females as stimulus
mice, KO displayed decreased social behavior in comparison to WT. A partition test (noncontact version
of the social interaction test) revealed no difference between KO and WT[94]. Despite some divergent
results most probably due to procedural differences, both groups concluded that social behavior is
abnormal in KO compared to WT.
A second group of core symptoms of autism concerns repetitive and stereotypic behaviors, resistance
to change, and restricted activities. To date, perseverance is the only aspect that has been investigated,
mostly on a B6 genetic background. It has been studied by the rate of extinction following training to
swim to a platform in various types of water mazes. Three of the studies found that Fmr1 KO mice had
significantly longer latencies to reach the changed position of a platform after learning an initial
position[82,89,96], whereas two other studies did not find any differences with WT[97,98]. Van Dam and
colleagues[98] used a cross-shaped water maze and found that although escape latencies were similar to
WT, Fmr1 KO mice made significantly less correct trials. These results seem to indicate that KO animals
are less flexible than WT and tend to persist in a once learned habit longer.
Regarding the variable symptoms of autism, most tests conducted on Fmr1 KO mice concerned the
murine equivalents of anxiety, mental retardation, hyperactivity, and idiosyncratic responses to sensory
stimuli (Table 2). Some features were found to be altered, but some showed no differences. Anxiety is
very often observed in autistic people and is linked to the impairment in anticipation that is thought to be
the origin of ritualistic behaviors[3]. This feature could also possibly be due to an alteration of amygdala
function[99]. An amygdala defect seems indeed to be present in Fmr1 KO mice as indicated by a trace
fear conditioning deficit[100] and altered social interactions. Most classical anxiety tests did not show any
differences between KO and WT[98,100,101,102], however, or KO were found to be even less anxious
than WT[82,91,94,101]. Abnormalities in corticosterone levels in response to restrain stress have
nevertheless been shown[103,104], resulting in altered negative feedback regulation of the glucocorticoid
response. In consequence, Fmr1 KO mice present a delayed response to stress and are also slower to
return to baseline[104]. FMRP binds to the glucocorticoid receptors and their expression was reduced in
the dendritic region of the Fmr1 KO mouse hippocampus[105]. It has indeed been reported that FXS
patients have a deregulated adrenopituitary axis[106].
Some studies on learning capacities indicated a deficit of KO mice in spatial learning tasks compared
to WT mice[82,83,98,102] while others did not report any deficit[83,91,97,101]. Deficits were found in
trace fear conditioning and were linked to LTP deficits in the lateral amygdala and cingulate cortex[100].
Similar deficits were found in Fmr1 KO on a mixed 129/FVB hybrid genetic background[102], which
were investigated in only this one study.
Motor abilities and aggression have been reported to be normal[91,101], but this may need further
exploration. Hyperactivity, however, seems to be the most consistent behavioral feature of Fmr1 KO mice
on a B6 genetic background[82,91,94,101]
although Nielsen et al.[107] reported no differences after a 5-
min observation in the open field. Hyperactivity in Fmr1 KO on a FVB/N background is still
controversial as they were reported not to be different from control mice[100] (as was the case in KO on
an FVBxB6 hybrid background[107]), but were significantly increased when test durations were longer
than 18 min[108].
Although no difference was found between KO and WT in nociception in response to heat, most other
responses to sensory stimuli were found to be altered in KO[100]. Koekkoek et al.[109] reported that

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conditioned eye blink reflex was altered in a Purkinje cell specific Fmr1 KO on a B6 background.
Auditory startle response also seems to be FMRP dependent; although KO on both FVB and B6
backgrounds displayed opposite responses, they were both significantly different from WT[73,101,107].
Finally, Fmr1 KO mice on both genetic backgrounds were radically more prone to audiogenic seizures
than their WT homologues[83,110].
CONCLUSIONS
The Fmr1 KO mouse model has been studied for several behavioral and physiological features relevant to
autism and appears to display most expected symptoms. Although mixed results have been obtained for a
few behavioral features, other autism-specific features are undoubtedly impaired. Most results up till now
have been obtained with KO animals on the B6 background. It should be noted that in spite of the
relatively scarce data, it is clear that FVB mice also are affected by the KO mutation of Fmr1, but present
a specific behavioral profile different from the one displayed by B6 KOs. In particular, the Fmr1 KO
mutation was shown to have opposite effects on the sizes of the hippocampal intra- and infrapyramidal
mossy fiber (IIPMF) terminal fields, depending on whether the mutation was expressed on a B6 or FVB
background[90,91]. These IIPMF seem to be implicated in several behaviors[111,112]. Thus, it should be
interesting to carry out more systematic studies in both the B6 and FVB backgrounds. This might render a
plastic and reliable model for autism that takes into account the variability of the disorder in humans.
Despite the foregoing, it is clear that much work remains to be done before Fmr1 KO mice can be
validated as a model for autism. In particular, social communication and cognitive rigidity have hardly
been investigated yet. Several variable features of autism, such as sleep disturbance, brain overgrowth,
developmental delays, and stereotypies, also need more detailed investigation.
In conclusion, the etiology of autism remains unknown and the limitations of research in humans
make it necessary to develop animal models for this disorder. These models must fit construct, face, and
predictive validity criteria. Several possible models exist, but few of them have been extensively studied
as yet. The current short review shows that not only does the Fragile X Syndrome have a symptomatology
resembling autism to a very large extent and that the validated genetic mouse model that is available for
this disorder, the Fmr1 KO mouse also shows much promise as a possible model for autism.
ACKNOWLEDGMENTS
Supported by grants from the March of Dimes (12-FY05-1198), Conseil Régional d’Aquitaine, CNRS,
and the University of Bordeaux I to WEC.
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This article should be cited as follows:
Bernardet, M. and Crusio, W.E. (2006) Fmr1 KO mice as a possible model of autistic features. TheScientificWorldJOURNAL 6,
1164–1176. DOI 10.1100/tsw.2006.220.