Experimental Models for Autism Spectrum Disorder Follow-Up for the Validity
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Rev J Autism Dev Disord (2016) 3:358–376 DOI 10.1007/s40489-016-0088-7 REVIEW PAPER Experimental Models for Autism Spectrum Disorder Follow-Up for the Validity Uma Devi1 & Vikas Kumar 1 & Pushpraj S Gupta1 & Suchita Dubey2 & Manjari Singh3 & Swetlana Gautam3 & Jitendra K Rawat3 & Subhadeep Roy 3 & Rajnish Kumar Yadav3 & Mohd Nazam Ansari4 & Abdulaziz S. Saeedan4 & Gaurav Kaithwas3 Received: 1 January 2016 /Accepted: 16 August 2016 /Published online: 12 September 2016 # Springer Science+Business Media New York 2016 Abstract Autism spectrum disorders (ASDs) are often con- Introduction sidered to be genetic. They are characterized by unificational behavioral abnormalities which are classified in two basic Autism spectrum disorders (ASDs) are complex domains: social relations and social communication, and re- neurodevelopmental disorders with uncertain pathogenesis de- stricted and repetitive pattern of behaviors and activity. fined by qualitative impairment in social interaction and social Clinical research has evidenced that genetic and environmen- communication, and restricted and repetitive patterns of behav- tal factors play a major role in the development of ASD, and it ior, interests, or activity. ASD exhibits high prevalence rate of 1– is contemplated to be a multifactorial as well. Augmentation 2 per 100 people. Consequently, ASD is the major serious prob- in the field of molecular genetics and neuroscience allows the lem worldwide. Moreover, it is reported that ASD is four times pharmacologist to explore more features of ASDs using ge- more frequently occurs in male than female and it is among the netic, humanoid, and nonhumanoid models. Hence, the pres- heritable disorders evident by family and twin studies with a ent review was undertaken to elucidate the major concepts concordance rate of 70–90 % for monozygotic twins (DiCicco- associated with the models of ASD, such as gene or chromo- Bloom et. al. 2006; Folstein and Rosen-Sheidley 2001;Bailey some incrimination; face, predict, and construct validities; be- et al 1995). The etiology of ASD is not well known, and it is havioral assays; and advantages and disadvantages of preclin- thought to be that brain development is affected which may be ical models along with constrains in developing genetic due numerous potential risk factors ranging from genetic to epi- models for ASD. genetic, to environmental. A number of genetic modifications which can increase the risk of developing ASD include muta- tions, chromosomal deletions, or duplication (copy number var- Keywords ASD .Mouse models . Maternaltoxicity .Genetic iation (CNV)) (Sebat et. al. 2007). Although ASDs belong to models human, since mice having similar kind of gene expression mouse models plays an important role in better understanding the etiol- * Gaurav Kaithwas ogy and the genetic aspect of ASD and thus help to develop more [email protected] effective therapies. Most of the characteristics of ASD-like defi- cits in social interaction and communication, and repetitive and 1 Department of Pharmaceutical Sciences, Faculty of Health Science, stereotyped motor behavior are modeled in mice (Crawley 2004, Allahabad Agricultural Institute- Deemed to be University, Sam 2007a, b). Advances in the fields of experimental genetics and Higginbottom Institute of Agriculture, Technology and Sciences, Allahabad 211007, Uttar Pradesh, India molecular biology have led to the development of various genet- ically modified mouse models targeting various genes associated 2 Department of Pharmaceutical Sciences, Amity University Campus, Lucknow 226028, Uttar Pradesh (U.P.), India with ASD, and other animal models induced by drug adminis- tration, surgical injury, or viral infection are developed with path- 3 Department of Pharmaceutical Sciences, School of Bioscience and Biotechnology, Babasaheb Bhimrao Ambedkar University (A central ophysiological and genetic aberration characteristics of human University), Lucknow 200 265, Uttar Pradesh, India clinical disorders. The models can be tremendously beneficial for 4 Department of Pharmacology, College of Pharmacy, Prince Sattam enumerating disorder etiology, effects on organic and cellular Bin Abdulaziz University, Al-Kharj, Kingdom of Saudi Arabia function, and therapeutic efficacy of novel treatment strategies. Rev J Autism Dev Disord (2016) 3:358–376 359 The present review describes the major mouse models and re- VPA, and maternal immune activation (MIA) with cently developed nonhuman primate models along with their polyinosine/cytosine, lipopolysaccharide (LPS)-induced neu- important features that have been developed, and a brief descrip- ropathology, terbutaline-induced hyperactivity along with 5- tion on behavioral assays was used to study ASD (Table 1). The methoxy tryptamine-induced ASD (Grabrucker 2013; review also explores the validity of these models, i.e., the face, Folstein and Rosen-Sheidley 2001). In this section, we have predict, and construct validity, where face validity is used to discussed rodent models of maternal risk factors. assess behavioral phenotypic similarities of the model, construct validity determines the potential of the model to mimic the path- PolyI:C Induced ophysiology of the disorder, and predict validity takes about the pharmacological similarity of the model (Table 2). Polyinosine/cytosine (PolyI:C) is synthetic, double-stranded RNA that evokes an antiviral-like immune reaction by maternal immune activation. The polyI:C MIA model has been exten- Models of ASD sively studied with regard to the behavior of the offspring, as well as their neuropathology, neurochemistry, structural MRI, ASD is a complex neurodevelopmental disorder with no sin- and more recently, electrophysiology (Patterson 2009;Meyer gular pathology (heterogeneous in nature). Since mice have et al. 2011; Hsiao et al. 2011). The offsprings exhibit deficits in comparable similar kind of genetic expression to humans ultrasonic vocalizations (USVs), USVs emitted by altricial ro- (98 % of human genes), this makes an excellent model to dent pups are whistle-like sounds with frequencies between 30 understand the various diseases. Various animal and geneti- and 90 kHz (Branchi et al 2001). Measurement of USVs ap- cally modified models are designed to modeling the core fea- pears to be a promising strategy in order to determine the com- tures associated with the ASD in order to understand the munication deficits of rodent, self-grooming, marble burying, mechanism underlying the ASD. Rodents are widely used to and perseveration in the water maze reflecting the behavioral screen the drugs, study the mechanisms, and study the under- similarities to the core symptoms of ASD like increased lying pathology for ASD. Both the regular/routine (e.g., repetitive/stereotyped motor behaviors along with deficits in Sprague-Dawley, albino Wistar, Norway rats, etc.) and null/ social interaction and communication (Patterson 2009;Hsiao knockout (KO) (e.g., OT and AVP KO, FMR 1KO, etc.) ro- et al. 2011). The offspring also displays a number of other dents are used to study the various aspects of ASD. The null or behaviors found in subsets of ASD subjects such as difficulty KO rodents are the ones where a specific gene has been kept with changes, insistence on sameness, enhanced anxiety, and silence (null) or has been removed (KO). Such animals are eye blink conditioning (Patterson 2009; Dammann and Meyer preferably used to study the function and behavior of a partic- 2001). ular gene and thereby hold a very significant space in the ASD research. However, it is difficult to generate animal model that LPS-Induced Neuropathy displays all the features of ASD because of the multifactorial nature. In this section, we have covered the animal models Maternal LPS administration yields offspring which mimics induced by maternal risk factors, genetically modified mouse the infection by gram-negative bacteria. The neuropathology model, and humanoid and nonhumanoid models that display in the LPS model ranges from severe to very mild, which many of characteristic features of ASD to better understand depends upon the treatment protocol. The increased cell den- this complex disorder. sity and limited dendritic arbors in the hippocampus are major Pathophysiological associations with this model (Baharnoori et al. 2009). The behavioral patterns include fewer ultrasonic Environmental Toxicant USVs (communication), less play behavior including pinning, sniffing the partner, crawls over/under the other animal, and It has been suggested that prenatal exposure of environmental partner mounting. The prenatal LPS exposure results in social toxicant affects the developing brain which increases the risk deficits, communication abnormalities, and cognitive inflexi- of developing ASD. Indirect evidences are found with expo- bility, i.e., ASD-like effects (Pinheiro et al. 2012). sure of external environmental toxicants like lead, ethyl alco- hol, methyl mercury, arsenic, organophosphate insecticides, VPA-Induced ASD DDT, and polychlorinated biphenyl while evidence-based studies are available with the exposure to thalidomide, Women taking VPA for mental illness or epilepsy during early valproic acid (VPA), misoprostol, infection with influenza vi- pregnancy are at elevated risk for ASD, and the same has been rus, rubella virus, and cytomegalovirus. Rodent models devel- exploited as a model for preclinical screening (Markram et al. oped for the risk factors include maternal respiratory infection 2007; Schneider et al. 2008; Hsiao