**5. Mouse models for autism research**

Mouse models provide a powerful strategy to explore experimentally candidate genes for autism susceptibility, and to use environmental challenges to induce gene mutations and cell pathology early in development. Mouse models have also been used to investigate the effects of alterations in signaling pathways on neuronal migration, neurotransmission and brain anatomy, which are relevant to findings in autistic subjects [250]. These models have elucidated neuropathology that might underlie the autism phenotype.

There are currently several mouse models for autism research, most of which are primarily developed by knocking out different candidate genes for other neuropsychiatric diseases such as fragile X syndrome [250, 251], Rett syndrome [252], but now are used as autistic models because of their autistic-like behaviors. Other examples include *Engrailed 1&2* and *PTEN* genetic mice [253, 254]. In addition, there is another group of models constructed by surgical or toxic treatments of candidate regions in the brain, in general during development [255]. Some other reports regarding autistic-like behaviors in BALB/c and A/J mice have also been seen [250, 256-258].

Here the author would like to stress an inbred mouse strain for autistic research. BTBR T(+)*tf/J* mouse, also named as BTBR mouse, is an inbred strain with black top coat and blond undercoat. Anatomically BTBR mice get total absence of the corpus callosum, and severely reduced hippocampal commissure, which are also attributed to their phenotypes [259-262]. Although primarily used as type 2 diabetes model [263-268] and phenylketonuria (PKU) model [269-274], BTBR mice were recently found to be a promising mice model for autism research because they exhibited the three core symptoms for diagnosing autism [275-282]. Using this strain, several groups have begun to explore the pathogenesis of autism. It was well documented that circulating corticosterone is higher in the BTBR than in B6. And higher basal glucocorticoid receptor mRNA and higher oxytocin peptide levels were detected in the brains of BTBR as compared to B6, although their relationship to autism remain disputable [283, 284]. In the meanwhile, potential treatments for autism have been proposed based on the experimental results using BTBR mice. Two independent groups confirm the efficacy of the SERT blocker, fluoxetine for enhancement of social interactions [285, 286]. Another experiment reported repetitive self-grooming behavior in the BTBR mouse model of autism was blocked by the mGluR5 antagonist Methyl-6-phenylethynylpyridine (MPEP) [287]. Behavioral therapies offer another option for autism treatment, Young group reported social peers rescued autism-relevant sociability deficits in adolescent BTBR mice, but not cross-fostering [288, 289].

However, the tools to analyze these animals are not yet standardized, and an important effort needs to be made. Crawley *et al* proposed three standards to evaluate animal model, namely face validity (i.e. resemblance to the human symptoms), construct validity (i.e. similarity to the underlying causes of the disease) and predictive validity (i.e. expected responses to treatments that are effective in the human disease) [290]. Using these standards, newly developed tests are used to screen more animal models for autism research.

#### **6. Summary and conclusions**

Autism spectrum disorders (ASD) is a common neurodevelopment disorder. Diagnosed before three years old, autistic children present significant language delays, social and

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communication challenges, as well as abnormal repetitive and restrictive behaviors. It is reported that ASD occur in all racial, ethnic and socioeconomic groups, yet are about four times more likely to occur in boys than in girls probably due to the extremes of typical male neuroanatomy of autism.

The relationship between immune disorders and ASD has been proposed based on series of evidences.Secondly, genetic predisposition is considered to be involved in the etiology of ASD. Cumulative evidences indicated ASD had a strong genetic background, both genegene and gene-environment interactions attribute to the etiology of autism. Also, it's now generally accepted that ASD is a group of multi-genetic diseases, in which environmental factors play an important part. Given the early onset of the symptoms, prenatal exposures to environmental challenges are considered the major risk factors leading to subsequent mortality of ASD. Various factors have been proven to be potentially detrimental to early neurosystem development, including maternal use of pharmaceutical agents with neurotoxic effects, intrauterine exposure to viral infections or maternal stress , as well as exposure to high levels of environmental pollutants such as heavy metals . Similarly, neonatal exposure to such risk factors may also lead to mortality of ASD, which has been proven in animal studies as well as clinical reports.

At last, ASD animal models provide a feasible and relatively easy way to morphologically and functionally study the etiology of ASD in different levels, and to testify the effectiveness of the potential interventions. Recent advances in this field provide both inbred strains such as BTBR *T+ tf/J* mice and mutant lines. Other mice models for fragile X syndrome, Rett syndrome have also been used for autism related studies due to the autistic-like behaviors exhibited in these patients.

In conclusion, data remain inconclusive for the majority of candidate genes tested so far. Still, we have good reason to be optimistic regarding gene discovery in ASD now and in the future. Cytogenetic, linkage, association studies and array analysis have provided promising results. Emerging genetic technologies and analysis tools offer even more powerful approaches for developing insights into the etiology of ASD. In addition, genetic studies facilitate other autism research such as biochemical and neuroimaging studies, which will, in turn, provide evidence and valuable clues to direct future genetic studies.
