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 et al. 2011). In pregnant rats, with influenza virus, behavioral abnormalities induced by a single injection of VPA results in behavioral abnormalities 360 Table 1 Screening models for autism spectrum disorders

S. no. Models Animal used Type of model Location of Validity Associated References chromosome characteristics Face Predict Construct

1 Environmental toxicant models 1.1 Polyinosine/cytosine Mouse Heterozygous – Yes Maybe Yes Ultrasonic vocalizations, (Patterson 2009; self-grooming Dammann and Meyer 2001; Hsiao et al. 2011) 1.2 LPS model (single Mouse Heterozygous – Yes Maybe Yes Fewer ultrasonic vocalization (Pinheiro et al.2012) prenatal exposure) (communication), less play behavior including pinning, sniffing the partner, crawls over/under the other animal, and partner mounting 1.3 Valproic acid Rat pups Homozygous – Yes – Yes Increased stereotypic/repetitive (Patterson 2009; behavior, decreased social Schneider et al. interaction, altered 2008) sensitivity to sensory stimuli, impaired PPI, elevated anxiety, impaired reversal learning, altered eye blink conditioning, and enhanced fear memory processing 1.4 Terbutaline Rat pups Homozygous – Yes Yes Yes Impaired school performance, (Bergman et al. 1984) cognitive dysfunction, and an increased incidence of psychiatric disorders 2 Neuropeptide models 2.1 Vasopressin (AVP) Brattleboro rats, Heterozygous Avpr1b gene Mixed Yes Yes Altered social interaction (Silverman et al.2010; V1aR KO mice Insel 2010;Ross V1bR KO mice, and Young 2009) 2.2 Oxytocin (OT) Oxytocin KO mice Chromosome 20 Mixed Yes Yes Altered social interaction and (Silverman et al. 2010; communication problem Insel 2010; Ross and

Young 2009) 3:358 (2016) Disord Dev Autism J Rev 2.3 Opioids Mu-opioid receptor ––Yes Yes Yes Altered social interaction and (Frescka and Davis KO mice communication problem 1991;Sher1997) 3 Genetic models A Models for genes associated with autism A3.1 Fragile-X mental retardation 1 Fmr1-null mouse Homozygous Xq27 Mixed Yes – Fragile-X syndrome (Moy et. al. 2006). (FMR 1): this gene provides information for making a protein FMRP. A3.2 Methyl-CpG-binding protein Mecp2-null mouse, Heterozygous Xq28 Mixed Yes – Rett syndrome (Chahrour and (MECP2): this gene Mecp2308/Y Zoghbi 2007) provides information for mouse making protein MeCP2. A3.3 Gamma-aminobutyric acid KO mouse Homozygous 15q11-13 No Yes Yes Angleman syndrome (Homanics et al. – receptor subunit β3 1997; DeLorey 376 (GABA β3) et al. 1998) e uimDvDsr 21)3:358 (2016) Disord Dev Autism J Rev Table 1 (continued)

S. no. Models Animal used Type of model Location of Validity Associated References chromosome characteristics Face Predict Construct

A3.4 Neurofibromatosis type 1 Nf1-null, Heterozygous 17q11.2 Yes No – Neurofibromatosis-1 (Costa et al. 2001) (NF1): this gene gives heterozygous, − − instruction for making a and NF123a / protein neurofibromin. mouse A3.5 7-Dehydrocholesterol Dhcr7-null and Heterozygous 11q13.4 Yes – Yes RSH/Smith-Lemli-Opitz (Wassif et al. 2001) reductase (DHCR7): heterozygous syndrome DHCR7 gene provides mouse

information for making – the enzyme 376 7-dehydrocholesterol reductase. vA3.6 Tuberous sclerosis 1 (TSC1) Tsc1-null mouse Heterozygous 9q34,16p13.3 Yes Yes Yes Tuberous sclerosis (Folstein and and tuberous sclerosis 2 Rosen-Sheidley (TSC2): TSC1 gene 2001) provides information for making a protein hamartin, while TSC2 for producing tuberin. A3.7 Phosphatase and tensin Mouse – 10q23.3 Yes Yes – Rett syndrome (Napoli 2012) homolog (PTEN): PTEN gene provides information for making a PTEN enzyme. A3.8 22q11.2 deletion syndrome Mouse – Chromosome –– Yes Velo-cardio syndrome (Gothelf et al. 2007) 16 A3.9 PRICKLE2 mutant mice Mice – PRICKLE 1 –– – Social deficits and (Hida et al. 2011) (prickle planar cell polarity and 2 gene enhanced spatial protein 2):PRICKLE2 gene memory encodes a homolog of drosophila prickle. Exact function of this gene is not known however mice studies suggested that it may involved in seizure prevention. A3.10 PAX6 KO mouse Paired box 6 Mouse – 11p13 –– – WAGR syndrome, (Szatmari et al. gene play a important role in decreased locomotor, 2007) the formation of organs and ataxia tissues during embryonic development. B Models for genes associated with cell adhesion proteins B3.1 Neurexin 1: this protein like Mouse Homozygous 2p16 Yes – Yes Normal anxiety related (Szatmari et al 2007; other neurexin proteins, behaviors, locomotor Zahir et al. 2008) contains epidermal growth activity, and spatial factor repeats and laminin G learning and memory domains 361 362 Table 1 (continued)

S. no. Models Animal used Type of model Location of Validity Associated References chromosome characteristics Face Predict Construct

B3.2 Contactin-associated protein Mouse Homozygous 7q35 Yes – Yes Altered social interaction, (Winslow et al. 2000; (CNTNAP2): this protein like restricted and repetitive DeLorey et al. 2008) other neurexin proteins, behavior contains epidermal growth factor repeats and laminin G domains B3.3 Cadherin protein: cadherin Mouse Homozygous 16q22 –– – Ultrasonic vocalizations (Winslow et al. 2000; protein is a class of type 1 (USVs), social DeLorey et transmembrane proteins and interaction, and display al. 2008) have role in cell adhesion. repetitive behavior B3.4 Shank 2: SH3 and multiple Mouse Heterozygous 11q13 Yes – Yes Down’s syndrome, (Won et al. 2012) ankyrin repeat domains Fragile-X syndrome protein 2 encoded by SHANK2 gene. B3.5 Neuroligin 3: neuroligin 3 gene Mouse Homozygous Xq13.1 Yes – Yes With less anxious, decrease (Chih et al. 2004; encodes a member of a family juvenile play, deficits in Comoletti et al. of neuronal cell surface sensory motor gating and 2004; Laumonnier proteins. increased preservation et al. 2004) behavior C Genetic models derived from human genetic studies C3.1 Engrailed 2: homeobox-containing En1 and En2 Homozygous 7p15 – No – Rett syndrome (Borzychowski et al. genes have a role in controlling (engrailed) null 2006; Gupta and development. mouse State 2007) C3.2 Homeobox A1 and A2 (HOXA1 Hoxa1-null Homozygous 7p15.3,7p15.2 No Yes Yes Asperger syndrome (Studer et al.1998) and HOXA2): in vertebrates, the mouse genes encoding the class of transcription factors homeobox genesarefoundinclusters namedA,B,C,andDonfour separate chromosomes

D Genetic models based upon 3:358 (2016) Disord Dev Autism J Rev rodent strains D3.1 BTBR mouse Mouse Homozygous – Yes – Yes Low sociability, (Amaralet et al. 2008; communication impairment Silverman et and stereotype or repetitive al. 2010) behaviors E Other genetic models E3.1 SERT (SLC6A4) (serotonin SERT-null and Heterozygous 17q11 Yes Yes – Decrease in ultrasonic (Schain and Freedman transporter gene): this gene heterozygous vocalizations, decreased 1961; Mulder et al. encodes an integral membrane mouse social interaction 2004) protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. E3.2 Homozygous – Yes Yes –– – 376 e uimDvDsr 21)3:358 (2016) Disord Dev Autism J Rev Table 1 (continued)

S. no. Models Animal used Type of model Location of Validity Associated References chromosome characteristics Face Predict Construct

Monoamine oxidase-A (MAO-A): MAO-A-null (Schain and Freedman MAO-A encode mitochondrial mouse 1961; Mulder et al. enzymes which catalyze the 2004) oxidative deamination of amines. E3.3 RELN (Reelin gene) Reeler mutant Heterozygous 7q22 No No Yes – (Fatemi 2005;Liu The RELN gene provides mice et al. 2001)

instruction for making a – protein called reelin . it 376 produce in brain before and after birth. E3.4 FOX P2(−/−)miceFOXP2 gene Mice Homozygous 7q31 –– Yes Difficulty in learning to produce (Mac Dermot et al. encodes a member of the the vocal movements needed 2005; Mulder, et forkhead/winged-helix (FOX) for speech, as well as al. 2004) family of transcription factors. extensive other language deficits 4 Neonatal infection model 4.1 Borna virus model Rat – Average – Average Social play deficits, cognitive (Netsler and Hymen deficits, development and et al. 2010) regional abnormalities 5 Humanoid model Mouse 15q11-13 Yes Yes Developmental abnormalities (Takumi 2010) and anxiety 6 Nonhuman primate model 6.1 Neonatal amylgdala lesion in Rhesus monkey ––Yes Yes Less overall activity, exploration (Bauman et al. 2010; Rhesus monkey of the test environment Bachelevier 1994) 6.2 Maternal autoantibody Rhesus monkey ––Yes (high) Possibly yes Yes (high) Whole body stereotype (Adolphs 2010; model in Martin et al. 2008) rhesus monkey 363 364 Rev J Autism Dev Disord (2016) 3:358–376

Table 2 Behavioral assays for screening of autism spectrum disorders

S. no. Behavioral assays References

A Inappropriate social interactions (Silverman et al. 2010;Vogel2002; Mathiasen Social approach to a stranger mouse; reciprocal social interactions; conditioned place and Dicamillo 2010) preference to conspecifics; preference for social novelty; social recognition Juvenile play; nesting patterns in the home cage; resident intruder interaction Partition test; social transmission of food preference B Impairments in social communication (Silverman et al. 2010;Vogel2002) Behavioral responses to social olfactory cues from conspecifics; deposition of social olfactory pheromones; vocalizations emitted during social interactions; responses to vocalizations from conspecifics; parental retrieval of separated pups; ultrasonic vocalizations by separated pups C Repetitive and restrictive behaviors (Silverman et al. 2010;Vogel2002; Rossi and Motor stereotypes, including circling, jumping and back flips; preservative Yin 2012; Bertholet and Cruscio 1991; hole board exploration; extinction of a learned response in an operant chamber; Givens et al. 1992; reversal of a position habit in an appetitive T-maze task; reversal of a position Henderson 1972;Payloretal.1993; Wenk et habit in an appetitive Y maze task; reversal of a position habit in the al.1984; Brioni and McGaugh 1988) Morris water maze; spontaneous responses to errors during reversal tasks; nose poke, hole board test Associated symptoms and behavioral tests for mice A Seizures (Silverman et al. 2010) Sensitivity to audiogenic seizures; sensitivity to drug induced seizures; observer scoring; electroencephalography (EEG) recordings B Motor clumsiness (Silverman et al. 2010) Balance beam foot slips; rotarod motor coordination and balance; footprint analysis C Aggression (Silverman et al. 2010) Resident intruder attack; Isolation induced fighting; tube test for social dominance D Sleep disturbances (Silverman et al. 2010;Vogel2002) Circadian running wheels; videotaped observations of home cage sleep and activity patterns; EEG recordings E Hypersensitivity and hyposensitivity to (Vogel 2002) sensory stimuli Acoustic startle; tactile startle; hot plate; Von Frey hairs; attentional neglect tape test; unresponsiveness to sensory attentional cues (failure to disengage attention) F Brain overgrowth (Silverman et al. 2010) Brain weight, volume, size of structures, and pathways; measurements at neonatal, juvenile, and adult time points G Developmental progression (Silverman et al. 2010) Developmental milestones in neonates; repeated testing of all relevant behaviors at juvenile and adult ages H Home cage observation; novel object test; behavior in an open field; marble (Hsiao et al. 1996;Mathisetal.1991; Morris burying test; self-grooming assay; exploratory locomotion in a novel open field; 1981; Morris et al. 1982; Gage et al. 1984; sniffing of novel objects Vo gel 2002;Belletal.2003; Wu and Melton 1993;Prestietal.2003; Yan et al. 2004; DeLorey et al. 1998; Turner et al. 2001; Silverman et al. 2010; Mehta et al. 2011) I Anxiety (Walf and frye 2007; Vogel 2002; Heinrichs Elevated plus maze; light ↔ dark exploration; Vogel conflict test; acoustic startle; and Koob 2005) ultrasonic vocalizations; marble burying; foot shock induced freezing J Theory of mind deficits (Silverman et al. 2010) Location of buried food following observation of conspecifics; social transmission of food preference task; avoidance of aggressive encounters K Intellectual disability (Vogel 2002; Bertholet and Cruscio 1991; Acquisition of Morris water maze tasks; acquisition of T maze tasks; Givens et al. 1992; Henderson 1972; contextual and cued fear conditioning; operant learning tasks; attentional Paylor et al. 1993;Wenketal.1984; measures on five choice serial reaction attentional task; hidden platform Rossi and Yin 2012;Sagoetal.1998; task; radial arm maze; active avoidance; passive avoidance Lalonde et al. 2004;Mineuretal.2002; Yan et al. 2004; DeLorey et al. 1998) Rev J Autism Dev Disord (2016) 3:358–376 365 such as increased stereotyped/repetitive behavior, decreased contact, declined pain sensitivity, insistence on sameness, and social interaction, altered sensitivity to sensory stimuli, elevated delayed developmental milestones (Panksepp 1979). anxiety, impaired reversal learning, altered (enhanced) eye- blink conditioning (Stanton et al. 2007;Patterson2011), and OT and AVP KO Mice enhanced fear memory processing, all of which are consistent with ASD in humans (Schneider et al. 2008;Patterson2009). It OT and AVP are two neuropeptides that play crucial roles in is interesting that maternal VPA exposure leads to reduced reproductive, social, and adaptive behaviors. Among their expression of neuroligin (an ASD candidate gene) in experi- firmly established roles in mammals, there is the ability of mental subjects (Kolozsi et al. 2009). Electrophysiological OT and AVP to make individuals to remember previously studies indicate that VPA offspring exhibit abnormal microcir- met individuals, i.e., a form of social recognition that is essen- cuit connectivity (Rinaldi et al. 2008), which may be related to tial to establish all complex relationships. The gene for AVP MRI studies showing impaired long-range functional connec- and OT are located on 20p11-12, and a single critical mutation tivity in individuals with ASD. There are also immune abnor- could influence the expression of both (Ross and Young 2009; malities such as decreased weight of the thymus, decreased Silverman et al. 2010; Insel 2010). The OT and AVPKO mice splenocyte response to stimulation, and a lower IFNγ/IL-10 reflect, impairment in social recognition has been observed ratio. Most of these abnormalities are found only in male off- confirming that the OT/AVP system is crucially involved in spring, which is consistent with the male bias in ASD incidence the processing of socially relevant cues. Thus, the OT/AVP (Schneider et al. 2008). system may represent a common end point at which several genetic alterations converge to produce the disturbance of so- Terbutaline-Induced ASD cial behavior, that is the hallmark of ASD (Ross and Young 2009;Insel2010). When terbutaline crosses placenta (Bergman et al. 1984)and by overstimulating β2-adrenoceptor (β2ARs) in the fetal brain, Opioid they can disrupt the replication and differentiation of develop- ing neurons (Slotkin et al. 2001). The use of terbutaline by the The opioid excess theory says that children with ASD are women during pregnancy showed impaired school perfor- symptomatic due to excess opioid-like substances, whose ef- mance, cognitive dysfunction, and increased incidence of psy- fects on the brain can produce the symptoms of autism. chiatric disorders in the offsprings (Feenstra 1992; Pitzer et al. Opioids and opioid-like substances, especially when in ex- 2001). Animals treated with terbutaline on postnatal 2 to 5 cess, exert many effects upon hormones and hormonal regu- showed consistent patterns of hyperreactivity to novelty and lation. A number of researchers have suggested that excessive aversive stimuli when assessed in a novel open field, as well brain opioid activity could explain the purported decreased as in the acoustic startle response test. Overstimulation of the pain sensitivity observed in ASD and contribute to or even β2AR by terbutaline results in microglial activation associated determine the pathogenesis of ASD (Frescka and Davis 1991; with innate neuroinflammatory pathways and behavioral ab- Sher et al. 1997). The opiate addicted animals exhibit less normalities. Postnatal β2AR stimulation by terbutaline can sensitivity to pain, less emotional status with stereotyped be- provide a useful animal model for ASD to facilitate understand- haviors, and social interaction impairments, the features of ing of neuropathology in this disorder and to develop potential ASD. The animals have also demonstrated reversal of ASD future treatments (Connors et al. 2005). However, the same has symptoms following administration of naloxone (Wimersma not been exploited to its full and needs to be explored further. Greidanus et al. 1988). However, the predict validity of these animal models remain to be ascertained, considering the in- consistent results of studies measuring opioid levels Mutated Neuropeptide Models (Tordjman et al. 1997) and the absence of clear benefits of opiate antagonist therapies (naloxone or naltrexone) in indi- The pharmacological and genetic manipulations of oxytocin viduals with ASD (Sandman et al. 1991; Sandman 1992; (OT) and vasopressin (AVP) have established the importance Willemsen-Swinkels et al. 1995). In fact, one study even of these neuropeptides in the regulation of complex social be- found that naltrexone actually increased stereotyped in ASD haviors. Moreover, functional alterations in these systems may (Willemsen-Swinkels et al. 1995). contribute not only to social deficits of ASD but also to repet- itive behaviors (Ross and Young 2009;Insel2010). In addition to this, researchers reported that peptides having opioid activity Genetic Models may involve in pathogenesis of ASD. Panksepp firstly ob- served that there are few similarities between the features of The etiology of ASD is poorly understood; however, involve- ASD and long-term effects of morphine like reduced social ment of strong genetic component is evident from the 70 to 366 Rev J Autism Dev Disord (2016) 3:358–376

80 % concordance between identical twins. Various genes like also develop a progressive neurological disorder with, surpris- FMR1, MECP2, tuberous sclerosis (TSC) 1, TSC2, HOXA-1, ingly, an enhancement in synaptic plasticity, motor, and con- HOXA-2, RELN, MAO-A, WNT-2, NF1, 3β-hydroxysteroid textual learning skills between age 10 and 20 weeks, and, at an Δ7-reductase (DHCR7), and SERT have been identified to be older age, hypoactivity, seizures, and abnormal forelimb linked with ASD (Moy et al. 2006). The genetic linkage has clasping, all of which are reminiscent of human RT syndrome been very well exploited by targeted disruption or mutation of (Chahrour and Zoghbi 2007). a specific gene to develop various models for ASD. Due to large numbers of associated loci with ASD, the most common strategy for genetic modification is by generating a null allele GABRB3-Deficient Mice or target disruption, which a portion of locus is disrupted and thereby form a nonfunctional protein. The other strategy is to Impairment of GABAergic transmission contributes to the design an allele, associated with disease in humans. The ge- development of ASDs. GABA is the main inhibitory neuro- netic mouse models discussed below are both targeted disrup- transmitter in adulthood and is released by interneurons which tion based and disease associated allele based. contain the GABA-synthesizing enzymes glutamic acid de- carboxylase (GAD) and GAD67 (IMGSAC 2001). FMR-1 KO Mouse Dysfunction of GABAergic signaling mediates ASD-like ste- reotyped in the majority of animal models and is obtained by The FMR1-KO mouse displays some core behavioral features experimentally manipulating candidate genes for ASD sus- of ASD and is considered to be one of the best animal models ceptibility or environmental risk factors. Mice lacking the β for ASD. Fragile-X syndrome is caused by mutations on the X GABA receptor subunit 3 (GABRB3) display high mortality ’ chromosome of gene fragile X mental retardation 1 (FMR-1). rate and symptoms consistent to Angelman s syndrome, in- The disorder shares a number of associated features in com- cluding learning and memory deficits, poor motor skills, ste- mon with ASD, intellectual disability, attention deficit hyper- reotyped behaviors, and seizure susceptibility (Homanics activity disorder, and epilepsy as associated behavior in ASD. et al. 1997; DeLorey et al. 1998). More recently, GABRB3 The fragile X leads to sever reduction in FMR1 protein ex- gene deficient mice have been shown to exhibit impaired so- pression which plays a role in RNA binding and transition cial and exploratory behaviors, deficits in nonselective atten- regulation. Fmr1 KO mice display some behavioral features tion, and hypoplasia of cerebellar vermal lobules, thus resem- of ASD including impaired social interaction and repetitive bling a wide range of ASD phenotypes (DeLorey et al. 2008). behavior along with cognitive and spatial learning deficits (Moy et. al. 2006). NF1 KO

MeCP 2 Mutant Mice NF1 KO mice are a model for neurofibromatosis (a genetic neurodevelopmental disorder that leads to nerve tumors, Rett syndrome (RT) is another genetic disorder that maps on X memory problems, and often, ASD) exhibits deficits in social chromosome, like fragile X syndrome. The disorder is mostly interaction and social learning (Costa 2002). NF1-KO mice prevalent in females and is marked by ASD-associated fea- through several behavioral tests are observed to have the most tures, like severe intellectual disability, slowed growth rate, dramatic difference with control mice in a test of Bsocial seizures, and hypoactivity and features characteristic of RT learning.^ Further, mice carrying a specific allele of Nf1 show such as stereotyped hand movements, abnormal breathing, deficient social transmission of food preference, impaired fear motor deficits, and scoliosis. The mutations in methyl-CpG- conditioning, spatial learning, and retarded acquisition of mo- binding protein (MeCP2) accounting for majority of cases tor performance on a rotarod, but without the increased tumor causing the disease are in the gene MeCP2. The allele found incidence (Costa et al. 2001). in the patient including either a missense mutation CP2 pro- tein is associated with the two global methods of transcrip- tional repression, i.e., protein binding to methylated CpG DHCR7 Null Mouse islands in genomic DNA and histone deacetylation. In the female mouse model of MeCP2 disruption, the mice appear DHCR7, the enzyme required for the terminal enzymatic step normal until about 16 weeks of age (a mouse typically is of cholesterol biosynthesis and the deficiency leads to Smith- mature by 4 weeks and dies at 2–3 years). Behavioral deficits Lemli-Opitz syndrome is an intellectual disability/ in these mice include enhanced anxiety in the open field, re- malformation syndrome with behavioral components of duced nest building, and aberrant social interactions. Genetic ASD. Dhcr7 gene modification (Dhcr7–/–) results in neonatal background modifies learning and memory performance also lethality and multiple organ system malformations (Wassif (Chahrour and Zoghbi 2007). Mice overexpressing MeCP2 et al. 2001). Rev J Autism Dev Disord (2016) 3:358–376 367

TSC Null Mouse Neurexin 1α KO Mouse

TSC is a genetic disease caused by mutation in either one of Neurexin 1 is part of a three-member family of genes coding the two genes, TSC1 and TSC2. for proteins involved in communication between neurons. It is Cerebellum has been identified as a key area where the link associated with glutamate, the neurotransmitter known to ele- between TSC and ASD resides. Deleting TSC gene in animals vate neuronal activity and play a role in early wiring of the produces signs of ASD symptoms including abnormal social brain. The model contains a biallelic deletion of the neurexin 1 interaction, repetitive behavior, and abnormal communication (Nrxn1) gene, and the same has been associated with ASD. (Folstein and Rosen-Sheidley 2001). The model is useful for understanding the role of neurexins in the development of ASD. The properties of neurexins sug- gested that they function as synaptic recognition molecules PTEN Mutant Mice (Ushkaryov et al. 1992) and mediate transsynaptic interactions via binding to neuroligins (Ichtchenko et al. 1995). Copy Phosphatase and tensin homolog on chromosome 10 (PTEN) number variations in the neurexin-1α gene (but not the is a protein encoded by PTEN gene which is a tumor suppres- neurexin-1β gene) were repeatedly observed in patients with sor gene. Defects in the PTEN gene have been sighted to be a ASDs (Szatmari et al. 2007; Zahir et al. 2008). The neurexin- potential cause of ASD. Hampered energy production in neu- 1α KO mice demonstrate normal anxiety-related behaviors, rons has been reported when defective PTEN gene interacts locomotor activity, spatial learning, and memory. Their motor with the protein of P53 gene. This leads to mitochondrial learning abilities are significantly enhanced. The mice is also DNA damage and abnormal level of energy production in observed with large increase in repetitive grooming behaviors, the cerebellum and hippocampus brain regions critical for so- indicating an abnormality with face validity, impaired sensory cial behavior and cognition (Napoli et al. 2012). Recently, a motor gating, and impairment in nest-building behaviors transgenic mouse line has been generated in which PTEN (Etherton et al. 2009). expression is cleverly deleted in restricted populations of neu- rons in the cerebral cortex (layers III–V) and dentate gyrus CNTNAP2 KO Mouse (granular layer and polymorphic layer) of the hippocampus (Kwon et al. 2006). These PTEN mutant mice display deficits The contactin-associated protein like 2 (CNTNAP2) is a in a wide range of social interaction and learning assays in- member of the neuronal neurexin superfamily that is involved cluding social interaction/learning, nest building, social pref- in cell-to-cell interaction and is associated with specific lan- erence test, and caged social interaction (Kwon et al. 2006). guage improvement and ASD. It is likely to play an important These deficits in social interaction and social learning are role in brain development (Alarcon et al. 2008). It is intriguing reminiscent of those observed in subject of ASD, which sug- that CNTNAP2 expression is elevated in circuits in the human gest that these animals have good face validity as a model of cortex that are important for language development. In addi- symptoms in the ASD social domain. Interestingly, PTEN tion, CNTNAP2 polymorphisms are associated with language mutant mice also exhibit neuroanatomical abnormalities that disorders, and the expression of this gene can be regulated by are hallmarked by a phenotype of progressive macrocephaly FOXP2, mutations in which can cause language and speech (Kwon et al. 2001). disorders (Panaitof et al. 2010). In light of these associations, a CNTNAP2 KO mouse model has been developed with strong association between ASD and allied neurodevelopmental dis- Tbx1 Heterogenous Mice orders. CNTNAP2 KO mouse shows deficits in communica- tion (USVs) and social interaction and display repetitive be- Congenic Tbx1 heterozygous mice exhibit lower levels of havior. These mice also exhibit several other features of ASD active and passive affiliative social interaction. Congenic HT like seizures, mild cortical laminar disorganization, and hyper- mice are impaired in affiliative social interaction at 2 months activity. The CNTNAP2 KO mouse model of ASD shows of age without confounding alterations in aggression, olfacto- striking parallels with human disease and is a new tool for ry investigation, or motor behavior. Alternatively or addition- mechanistic and therapeutic research in ASD (Vernes et al. ally, Tbx1 deficiency has demonstrated to alter prenatal/post- 2008). natal/adult neurogenesis. When individuals with 22q11.2 hemizygosity reach adulthood, defective working memory is SHANK-2 Mutant Mouse worse in those with schizophrenia than in those without it (Van Amelsvoort et al. 2004). Higher and increasing levels Shank 2 (also known as ProSAP1) is a multidomain scaffold- of anxiety are a risk factor for later developing schizophrenia ing protein and signaling adaptor enriched at excitatory neu- in 22q11.2 cases (Gothelf et al. 2007). ronal synapses. Mutations in the human SHANK-2 gene have 368 Rev J Autism Dev Disord (2016) 3:358–376 recently been associated with ASD and intellectual disability allogrooming compared to wild types. The differences in so- (Patterson 2011). Shank 2-mutant (Shank2−/−)micecarryinga cial behavior are reduced in adults; however, adult KO males mutation identical to the ASD-associated microdeletion in the display increased levels of autogrooming (repetitive) behav- human SHANK-2 gene exhibit ASD-like behaviors including ior. Deficits in spatial learning and memory tasks were detect- reduced social interaction, decreased social communication ed in En2 KO mice as well. Thus, the En2 KO mouse model by ultrasonic vocalizations, and repetitive jumping. These displays both face (social behavior disruption) and construct mice show a marked decrease in N-methyl-D-aspartate (cerebellar defects, genetic risk factor) validities. However, (NMDA) glutamate receptor (NMDAR) function. Shank2−/− the model does not presently suggest potential pharmacolog- mice showed impaired spatial learning and memory in the ical interventions to reverse these deficits (Borzychowski et al. Morris water maze test, impairments in social communication 2006). in USVs, and other ASD-like abnormalities like enhanced jumping mostly mixed with upright scrabbling, normal grooming, and decreased digging behaviors impaired nesting HOXB1 Mutant Mice behavior, hyperactivity in assays including the open field test, anxiety-like behavior in an elevated plus maze, and increased The HOXB1 gene, located on human chromosome 17q21.32, grooming in a novel object recognition arena (Goddard et al. is a member of the HOX gene family of homeobox transcrip- 1996). tion factors and is critically involved in the development of the brain stem. HOXB1 gene expression is limited to NLGN3 KO Mouse rhombomere 4 and to neural crest cells migrating out of this region, resulting in a gross reduction or complete loss of the Neuroligin (NLGN) 3 gene is encoded by neuroligin 3 pro- facial motor nucleus in HOXB1 mutant mice (Goddard et al. tein, a neuronal cell surface protein. Neuroligin is involved in 1996; Studer et al. 1996). HOXB1 gene expression occurs the formation and remodeling of central nervous system syn- very early in mouse development, at a time, interestingly, apse and are site-specific ligand for beta neurexin. Loss of overlapping with the window of maximal prenatal sensitivity function mutations in NLGN3 and NLGN4 have been found in rodent models of ASD (Courchesne 1997). HOXB1 gene in affected siblings with ASD, and these genes have been expression is also strongly upregulated by HOXA1 (Studer proposed to cause rare monogenic forms of ASD (Chih et al. et al. 1998) and the two genes indeed synergize in patterning 2004; Comoletti et al. 2004; Laumonnier et al. 2004). hindbrain structures, cranial nerves, and pharyngeal arches, so Neurexins, the binding partners for neuroligins, have also re- that double-mutant mice display prominent malformations cently been implicated as ASD susceptibility genes; a knock- while single mutants suffer much milder abnormalities out mouse approach has been employed to study the role of (Studer et al. 1998). A gene-to-gene interaction between neuroligins in synapse formation and function. NLGN3 KO HOXB1 and HOXA1 gene variants was initially proposed to rats exhibit complete loss of target protein (NLGN3) with less contribute to ASD (Ingram et al. 2000). anxious, decrease juvenile play, deficits in sensory motor gat- ing, and increased preservation behavior. It would be worth- while to mention that neuroligin 2 overexpressing transgenic BTBR Mouse also displayed stereotyped jumping, enlarged synaptic con- tact, and reduced GABA clustering along with anxiety-like The BTBR mouse strain shows phenotype relevant to the behavior (Etherton et al. 2009). diagnostic symptoms of ASD, i.e., low sociability, communi- cation impairment, and stereotypical or repetitive behaviors. En2 KO Mouse BTBR pups emit more and longer ultrasonic vocalization. Their repertoire of vocalization is also narrower in comparison Engrailed 2 (En2) is one of the most strongly linked gene to to pups from standard mouse strains. BTBR mice are associ- ASD. En2 encodes the protein involved in the development of ated with high blood levels of corticosterone accounting for cerebellum. Mice with the poor expression of En2 exhibit the exaggerated response to stress (Benno et al. 2009). Such abnormalities in cerebral circuits and cell membranes (Gupta enhanced stress could cause or aggravate the behavioral phe- and State 2007). En2 gene is located in a chromosomal region notype of these mice. Anatomically, BTBR mice lacks of the that is frequently abnormal in individuals affected with ASD. corpus callosum and a reduced hippocampal commissure Consistent with this, En2 KO mice display cerebellar hypo- (Silverman et al. 2010). Overall, a number of BTBR mouse plasia, a reduction in the number of Purkinje neurons in the behaviors are consistent with autism, and the most striking cerebellum and foliation defects, all of which is a parallel anatomical feature in this strain is consistent with many, but features observed in ASD. En2 KO juvenile males display a not all, studies of the corpus callosum in ASD (Amaral et al. reduction in play behavior, social interaction, and 2008). Rev J Autism Dev Disord (2016) 3:358–376 369

5-HT Transporter (SERT) Ala56 Mice and memory (Tao et al. 2011). Using the Bthree-chamber^ social test, the researchers also showed that unlike controls, Hyperserotonemia or increased whole blood serotonin [i.e., 5- the PRICKLE2 mutants spend significantly less time hydroxy-tryptamine (5-HT)] is a well-replicated biomarker inspecting a new mouse than a new object. that is present in approximately 30 % of subjects with ASD (Schain and Freedman 1961;Mulderetal.2004). The SERT PAX6 KO Mice gene (SLC-6A4) has been associated with whole blood 5-HT levels and ASD susceptibility. A genome-wide study of whole PAX6 is a pivotal player in brain development and mainte- blood 5-HT as a quantitative trait found association with the nance. It is expressed in embryonic and adult neural stem SERT encoding gene SLC-6A 4, as well as with ITGB-3, cells, in astrocytes in the entire central nervous system, and which encodes the SERT-interacting protein integrinβ3. In in neurons in the olfactory bulb, amygdala, thalamus, and both cases, the strongest evidence for association was found cerebellum, functioning in highly context-dependent manners. in males (Weiss et al. 2004, 2005; Carneiro 2008). Linkage Human PAX6 gene is originally identified in chromosomal studies in ASD also implicate the 17q 11.2 region containing region 11p13 as one related with WAGR (Wilm’stumor, SLC-6A 4, with stronger evidence in males (Sutcliffe et al. aniridia, genitourinary malformations, and intellectual disabil- 2005). The potential parallels of ASD-associated deficits in ity) syndrome which is a rare genetic disorder caused by chro- the SERT Ala56 mice have been observed, such as decrease mosomal deletion of the 11p12-p14 region. Recent studies in ultrasonic vocalizations, decreased social interaction, and have identified PAX6 mutations in individuals who manifest modest enhancement in the startle response during prepulse intellectual disability, aniridia, and ASD. Furthermore, chro- inhibition tests and rigid compulsive behavior. mosome 11p13, on which PAX6 is located, is implicated as a possible locus for ASD susceptibility by a linkage study REELER Mouse (Szatmari et al. 2007). Pax6c KO mice demonstrated a de- creased locomotor activity and ataxia due to defects in motor The RELN locus encodes a large glycoprotein that acts as a performance and prefrontal deficits. serine protease of the extracellular matrix (Fatemi 2005). REELER is an autosomal recessive mutant mouse with im- FOXP2 Mutant Mice paired motor coordination, tremors and ataxia, cortical lami- nation, abnormal positioning of neurons, and aberrant orien- No mutations in the gene coding region of FOXP2 have been tation (Falconer 1951). Analysis of the central nervous system directly linked to ASD, but the gene appears to regulate other in the mutant mouse revealed multiple defects such as inverted genes, such as CNTNAP2 and MET, which have been asso- cell bodies and fibers. The REELER mouse has been linked ciated with the disorder (Kurt and fisher 2012). Two geneti- with ASD along with other neuropsychiatric disorders includ- cally engineered strains of mice, each carrying a different ing schizophrenia, bipolar disorder, and depression (Fatemi FOXP2 mutation were developed recently. One strain carried 2001). Nevertheless, REELER mouse has been extensively the genetic glitch producing an error in a segment of the used as a mouse model for ASD. In addition to the FOXP2 protein that binds to DNA. The strain has difficulty abovementioned motor defects, REELER mouse also demon- in learning to produce the vocal movements needed for strated increase in anxiety, stereotyped behavior, social dom- speech, as well as extensive other language deficits. The mu- inance, and learning deficits (Lalonde et al. 2004). tation in the second strain was marked by a shortened version Heterozygous REELER mice were also found to have de- of the protein that disrupts its function altogether and was creased dendritic spine density (Liu et al. 2001) and reduced identified in another family with even more severe language levels of oxytocin receptors in the brain (Liu et al. 2005). deficits. Both mutant strains of mice have motor learning def- icits, trouble in mastering the auditory-motor association, im- PRICKLE2 Mutant Mice pairments in learning of motor skills, and loss of exploratory behavior, the features of ASD (Schain and Freedman 1961; The researchers found that mice lacking PRICKLE-2 have Mulder et al. 2004; MacDermot et al. 2005). social deficits and enhanced spatial memory, which is in- volved in the development of synapses, the junctions between neurons (Hida et al. 2011). Around the same time, a team of Neonatal Infection Models: Borna Virus Rodent collaborators found mutations in PRICKLE-2 and a related Models gene, PRICKLE-1, in people with myoclonus epilepsy, char- acterized by muscle twitching (Tao et al. 2011). PRICKLE-2 Borna disease virus (BDV) is an extremely neurotropic virus has been shown to be expressed all over the mouse brain, but that causes persistent and nonlethal infection of neural cells. especially in the hippocampus, a region important for learning BDV is an enveloped, nonsegmented, negative-sense, single 370 Rev J Autism Dev Disord (2016) 3:358–376 standard RNA virus of family Bornaviridae with in resulting in damage to amygdala and surrounding cortex Mononergavirales order. It causes wide spectrum of neurolog- (Bachevalier 1994). When placed in social pairs, the neonatal ical disorders in wide range of vertebrates. Lewis rats infected amygdala-lesioned infants showed less overall activity, explo- with BDV at birth survive because they fail to develop classi- ration of testing environment and social behavior initiation as cal antivirus cellular immune response to virus replication in compared to age-matched controls (Bauman et al. 2010). the brain. The pathological outcomes of neonatal BDV infec- However, the model does not demonstrate high face and con- tion include defects in the cerebellum and limbic system, hy- struct validity (Adolphs 2010). perreactivity, circadian rhythm disturbance, social play defi- cits, cognitive deficits, chronic anxiety, and developmental Maternal Autoantibody Model and regional abnormalities in serotonin and norepinephrine concentrations (Briese et al. 1994; De la Torre et al. 1996; Recent research has suggested that certain forms of ASD are Rubin et al. 1998; Carbone et al. 1991;Bautistaetal.1994, associated with maternal autoantibodies directed against fetal 1995; Pletnikov et al. 1999a, b, 2000, 2001, 2002; Hornig brain tissue proteins. Amaral and colleagues have evaluated et al. 1999). this model in Rhesus monkey (Martin et al. 2008). Behavioral observations of monkeys prenatally exposed to purified IgG from mothers of children with ASD showed more whole body Humanoid Model for Autism stereotyped than untreated control monkeys and monkeys pre- natally exposed to purified IgG from mother of typically de- Evidence suggested that abnormalities in chromosomes con- veloping children (Bauman et al. 2010). This model shows tribute to the risk of ASD and the duplication of human chro- high construct validity, moderate face validity, and if proved mosome 15q11-13 is most commonly involved in ASD. The successful, it could also demonstrate high predict validity as humanoid model for ASD is generated by interstitial duplica- the same is under development. tion in mouse chromosome 7c that is highly syntenic to human 15q11-13 by using a Cre-loxP-based chromosome engineer- ing technique. It is the first chromosome engineered mouse Zebrafish model for human chromosome 15q11-13 duplication that ful- fills not only the face validity of human ASD phenotypes but Zebrafish model is widely used for understanding the field of also construct validity based on human chromosome abnor- developmental biology (Dawid 2004; Halpern et al. 1995; mality. This model will be a founder mouse model for forward Hanneman et al. 1988; Vesterlund et al. 2011; Weis 1968), genetics of ASD and an invaluable tool for its therapeutic although it is not so popular model for understanding the development (Tatkumi et al. 2010). ASD as mouse model while fast oogenesis and embryo devel- opment allows rapid experimental assays. Additionally, trans- parency of embryo and development of embryo outside the Nonhumanoid Primate Models mother body allows for the study of growth and development of brain cell and tissues in the living embryo (Tropepe and Nonhuman primates share many features of human physiolo- Sive 2003). Zebrafish have similar kind of structural and func- gy, anatomy, and behavior; thus, it forms an ideal species to tional region as in ASD patient, so it is an outstanding model study a variety of human disorders like ASD, Parkinson’s used to disclose the genes involved in ASD, but the behavioral disease, and Alzheimer’sdisease,althoughitisinveryearly phenotypes associated with ASD are difficult to recapitulate stages of developing valid animal models of ASD have an (Dooley and zon 2000). Henceforth, other models are useful important role in understanding the ASD emergent of treat- for study the behavioral phenotypes associated with ASD. ment and prevention strategies. Nonhuman primates such as Many ASD genes such as DISC1, CHD8, MET, AUTS2, rhesus macaques (Macaca mulatta)share90–93 % alignment FMR1, SYNGAP1, and SHANK3 are studied in zebrafish of nucleotide sequences with humans. The advantage with this (Elsen 2009; De Rienzo et al. 2011; Bernier et al. 2014; model lies in similarities with human physiology, anatomy, Gauthier et al. 2010). and complex social behavior (Bauman et al. 2010; Capitanio and Emborg 2008; Burns et al., 1983). Songbirds Neonatal Amygdala Lesions Communication problem (both verbal and nonverbal) is the The nonhuman primate models of ASD developed by core characteristic in children with ASD. Understanding the Bachevalier was primarily based on study of six peer reared vocal learning by the songbirds appears as an excellent model monkeys that received aspiration lesions of amygdala, to study the stereotype aspect of ASD. Songbird model can be Rev J Autism Dev Disord (2016) 3:358–376 371 used both as a molecular and a behavioral model to understand understanding the cellular and molecular mechanism behind the human speech and language development (Banerjee et al. the language development in the human. 2014). Mutation in a FOXP2 gene is related to speech and language disorder, and the distribution of FOXP2 gene is re- markably similar as in the brain of both human and songbird, Behavioral Manifestations of ASD and Respective mainly in the subregions responsible for the learning and pro- Screening Assay duction of vocalization. CNTNAP2 gene is involved in hu- man language-related circuits (Alarcon et al 2008) and plays The Diagnostic and Statistical Manual for Mental Disorders important role in vocal communication in human as well as (DSM) in May 2013 published DSM-V supersending DSM- songbirds (Panaitof et al 2010). In the lack of models for vocal IV-TR. Within DSM-V, diagnoses classified as autism, communication, this model might play very crucial role in Asperger syndrome, PDD-NOS, and childhood disintegrative

Fig. 1 Overview of autism spectrum disorders. TS tuberous sclerosis, 4 (serotonin transporter), CNTNAP2 contactin-associated protein 2, EN 2 ReTT Rett syndrome, Avrp1 vasopressin receptor, Cadps2 calcium- engrailed-2, Met tyrosine kinase/hepatocyte growth factor receptor, dependent secretion activator 2, Gabrb3 GABA A receptor beta3 Foxp2 Forkhead box protein 2, PTEN phosphatase and tensin homolog, subunit, Oxtr oxytocin receptor, Slc6a4 solute carrier family 6, member CAM complementary and alternative therapies 372 Rev J Autism Dev Disord (2016) 3:358–376 disorder are generalized as ASD. As per DSM-V, the symp- communication in primates as well. Quantitative measure- tomatic features of ASD are classified into two major domains ments of reward value of social interaction are yet to be a brief outline of the domains associated with ASD is enumer- modeled. However, the advantages associated with mouse ated in Fig. 1. The symptoms of domain I concerned with models are cost-effectiveness, short gestation period, large impairments in social relations and social communication .A number of litters, time effectiveness, and rapid results. At the battery of behavioral assays are available to screen the domain same time, it is worthwhile to mention that mouse models I, including reciprocal social interaction, social transmission show low face validity and poor construct validity due to of food preference, social approach to stronger mouse, vocal- chartless etiology. Alignment of nucleotide sequences in ro- izations during social interaction, parental retrieval of separat- dents is entirely different from humans; therefore, predict va- ed pups, deposition of social olfactory pheromones, etc. lidity is low as well. Another major disadvantage with mouse (Table 2). The symptom domain II is concerned with restric- model is prefrontal cortex (a major ASD affected area) is tive interests and repetitive behaviors or activities. Individuals poorly developed in rodents. with ASD have preoccupations, which could be of abnormal intensity. The repetitive behaviors are also associated with Acknowledgments All the authors are thankful to the University self-injury-associated features like pocking own eye, skin Grants Commission, India. picking, hand biting, hand banging, and head banging Compliance with Ethical Standards (Fig. 1). This domain includes behavioral assays as more ste- reotyped, including circling, jumping and back flips, preser- Conflict of Interest The authors declare that they have no conflict of vative hole board exploration, etc. (Table 2). In addition to the interest. two core symptom domains, there are a number of symptoms associated with ASD. In particular, anxiety, hyperactivity, Research Involving Human Participants and/or Animals This arti- short attention span, irritability, mood instability, aggression, cle does not contain any studies with human participants or animals per- formed by any of the authors. self-injurious behavior, and poor impulse control and in addi- tion, sensory sensitivities as to sound, sight, smell, taste, or Informed Consent Informed consent is not required since the review touch certain stimuli is also associated with ASD. The associ- article does not contain any studies with human participants or animals. ated symptoms for ASD are screened as per the subdomains. The symptoms like anxiety, mind deficits, and intellectual disability can be screened using elevated plus maze test, vogel conflict test, and many more. In fact, the screening is entirely dependent on the type of the subdomains to be explored. 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