Advances in Behavioral Genetics: Mouse Models of Autism
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Molecular Psychiatry (2008) 13,4–26 & 2008 Nature Publishing Group All rights reserved 1359-4184/08 $30.00 www.nature.com/mp FEATURE REVIEW Advances in behavioral genetics: mouse models of autism SS Moy1 and JJ Nadler2 1Neurodevelopmental Disorders Research Center, Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA and 2Neurodevelopmental Disorders Research Center, Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Autism is a neurodevelopmental syndrome with markedly high heritability. The diagnostic indicators of autism are core behavioral symptoms, rather than definitive neuropathological markers. Etiology is thought to involve complex, multigenic interactions and possible environmental contributions. In this review, we focus on genetic pathways with multiple members represented in autism candidate gene lists. Many of these pathways can also be impinged upon by environmental risk factors associated with the disorder. The mouse model system provides a method to experimentally manipulate candidate genes for autism susceptibility, and to use environmental challenges to drive aberrant gene expression and cell pathology early in development. Mouse models for fragile X syndrome, Rett syndrome and other disorders associated with autistic-like behavior have elucidated neuropathology that might underlie the autism phenotype, including abnormalities in synaptic plasticity. Mouse models have also been used to investigate the effects of alterations in signaling pathways on neuronal migration, neurotransmission and brain anatomy, relevant to findings in autistic populations. Advances have included the evaluation of mouse models with behavioral assays designed to reflect disease symptoms, including impaired social interaction, communication deficits and repetitive behaviors, and the symptom onset during the neonatal period. Research focusing on the effect of gene-by-gene interactions or genetic susceptibility to detrimental environmental challenges may further understanding of the complex etiology for autism. Molecular Psychiatry (2008) 13, 4–26; doi:10.1038/sj.mp.4002082; published online 11 September 2007 Keywords: Angelman syndrome; fragile X; repetitive behavior; Rett syndrome; serotonin signaling; social interaction Introduction by multiple genes, and possible environmental factors, leading to aberrant neurodevelopment.7–11 Autism is a severe neurodevelopmental disorder that A complex combination of genetic predisposition is typically diagnosed by age 3. Twin studies have and environmental contribution may underlie the provided evidence for a markedly strong genetic broad range and differential severity of symptoms component for autism, with concordance rates as in autism. 1 high as 70–80% between monozygotic twins. Hetero- In recent years, mouse models have been developed geneity of the clinical syndrome suggests that the that reflect genetic alterations associated with autism. autism domain may encompass several disorders Some mutant lines are based on monogenic aberra- with different genetic profiles. Core symptoms tions, such as loss of Fmr1, methyl-CpG-binding of autism include profound deficits in social interac- protein-2 (Mecp2)orubiquitin protein ligase 3A tion and communication, restricted interests, stereo- (Ube3A) function, that underlie syndromes associated typed responses and other repetitive patterns of with autistic-like behavior. Other mutant lines are 2,3 behavior. Other abnormalities include high preva- relevant to loci for autism susceptibility, identified by lence of mental retardation, with rate estimates of association or linkage studies in human populations. 4,5 40–55% or higher, and co-morbid epilepsy, observed Mouse models have also been produced by prenatal 6 in approximately 30% of autistic subjects. These or neonatal environmental challenges, including early symptoms underscore the catastrophic consequences exposure to valproic acid or inflammatory agents, that of the genetic inheritance for brain function and have been suggested as autism risk factors by clinical behavior. Disease etiology is thought to involve an surveys. This review describes recent advances in the interaction between genetic susceptibility, mediated behavioral validation of mouse models for autism, and how mutant lines have been used to elucidate the Correspondence: Dr SS Moy, Neurodevelopmental Disorders molecular mechanisms underlying the functional Research Center, Department of Psychiatry, CB# 7146, University effects of genetic and other changes. The review also of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. E-mail: [email protected] examines how models for alterations in signaling Received 21 March 2007; revised 23 July 2007; accepted 31 July pathways can indicate novel genetic targets for 2007; published online 11 September 2007 studies of autism spectrum disorders. Mouse models of autism SS Moy and JJ Nadler 5 Behavioral phenotyping of mouse models vioral phenotyping protocols that can evaluate whether a specific mouse model recapitulates the The primary diagnostic indicators of autism are time course of disease onset.31–33 Wagner and collea- abnormal behaviors, rather than biochemical, neuroa- gues34,35 investigated abnormalities in neonatal and natomical or other physiological indices.3 Determin- juvenile mice relevant to neurodevelopmental dis- ing whether a proposed mouse model for autism orders using sets of behavioral tasks for sensorimotor recapitulates one or more of the core clinical symp- abilities, learning and memory, and other functional toms can provide valuable insight as to the functional domains. The researchers utilized a test for juvenile impact of altered genes or environment.12–16 However, play to reveal reduced social interaction in a genetic the development of mouse behavioral assays for model for autism, the Engrailed 2 null mouse.34 Adult detecting aberrant social responses, restricted inter- mutant and wild-type mice were assayed with the ests, or repetitive behavior reflective of autism has same interaction test, as well as a resident-intruder proved challenging. Our research group has proposed paradigm, to confirm chronic changes in social a set of behavioral tests that can be used to assess behavior in the mouse model. Other researchers have social deficits and repetitive behavior in mice.17–19 measured ultrasonic vocalizations in mouse pups The testing screen includes assays for social approach separated from their mothers as a test for and preference for social novelty, in which mice altered emotional behavior early in postnatal are offered a choice between different types of social life (Table 1).36–46 In most (but not all) of these and non-social stimuli. These choice tasks have studies, mouse pups with genetic alterations relevant provided evidence that sociability and social avoid- to social behavior had decreased levels of ultrasonic ance are dependent on genetic background. For vocalizations. These findings suggest that the vocali- example, mice from C57BL/6J and FVB/NJ inbred zation assay may be useful to measure attenuated strains, but not from the A/J, BALB/cByJ or BTBR responses to social isolation in neonates. Further, T þ tf/J inbred strains, demonstrated significant pre- since the vocalizations may be viewed as distress ference for proximity to another mouse rather than calls to elicit maternal intervention, deficits may being alone.17–19 Overall, inbred strain phenotypes model the early impairments in communication vary across a continuum of social behavior, with characteristic of autism. extremes of high social preference and overt social However, studies in early development are particu- avoidance.17,20–22 larly challenging to conduct. For example, Hahn and The symptom of repetitive behavior encompasses Lavooy,47 in a review of methodology for ultrasonic both ‘lower-order’ motoric stereotypy and self-injury, vocalization and maternal pup retrieval studies, and ‘higher-order’ responses reflecting general cogni- enumerate the many subject and experimental vari- tive rigidity, such as restricted, obsessive interests and ables that need to be carefully considered in the strong resistance to environmental change.13,23,24 Both design of neurodevelopmental evaluations. Difficul- components of the repetitive behavior domain tend to ties with neonatal behavioral assessments include a co-occur in children with autism or related disor- limited behavioral repertoire in very young pups, ders.23,25–27 A recent study examining the relationship stressful effects of repeated handling or maternal between core symptoms of autism in twins provided separation, and alterations in dam behavior caused evidence that, while highly heritable, the domains of by repeated disturbance of the home cage. Ognibene social impairment and repetitive behavior were ge- et al.,38 in a study on neonatal behavior in reeler netically heterogeneous.28,29 These findings raise the (Relnrl/rl) mice, evaluated behavior in both pups and intriguing possibility that mouse models reflecting dams. The researchers reported profound deficits in different components of the autism behavioral pheno- the number of ultrasonic vocalizations emitted by type might be used to distinguish the specific genetic male Relnrl/rl mice, in comparison to Reln þ / þ or pathways that mediate stereotypy and cognitive Relnrl/ þ mice. These phenotypic differences in ultra- inflexibility from those underlying deficiencies in sonic vocalizations, and less