Biology:Animal model of autism

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Short description: Approach to study autism

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An animal model of autism is a research approach that uses non-human species to investigate specific biological and behavioral features associated with autism spectrum disorder (ASD).[1] Rodent models are often used since their brains are similar to humans in makeup and because they have similar social interactions and structures. Given the complexity of autism and its etiology, researchers often focus only on single features of autism when using animal models.[2] For example, researchers may examine the mechanisim by which the disorder develops, environmental factors that can correlate to predispositions for ASD, or chromosomal factors.

Rodent model

Rodent models for autism include the Norway rat (Rattus norvegicus),[3] the mu opioid receptor knockout mice, and the Fmr1 knockout mice, which are also used as animal models of Fragile X syndrome.[4] More recent research has used the house mouse (Mus musculus) to model autism because it is a social species.

The Norway rat has been used in early studies exploring potential links between thiomersal and autism, such as work by Mady Hornig.[5][6] However, the current scientific consensus finds no compelling evidence supporting a causal relationship between thiomersal and autism,[7][8] and major scientific and medical bodies such as the Institute of Medicine[7] and World Health Organization[9] as well as governmental agencies such as the U.S. Food and Drug Administration[10] and Centers for Disease Control and Prevention[11] reject any role for thiomersal in autism or other neurodevelopmental disorders.

Behaviors measured in these models include approach to olfactory pheromones emitted by other mice, approach to familiar and new conspecifics, reciprocal social interactions, ultrasonic vocalizations, communal nesting, sexual and parenting behaviors, territorial scent marking, and aggressive behaviors, as well as motor behaviors such as gait.[12][13] Social interaction is measured by how the mouse interacts with a stranger mouse introduced in the opposite side of a test box.[14]

Researchers from the University of Florida have used deer mice to study restricted and repetitive behavior such as compulsive grooming, and how these behaviors may be caused by specific gene mutations.[15] In addition, Craig Powell of the University of Texas Southwestern Medical Center, with a grant from Autism Speaks,[16] is currently using mice to examine the potential role of neuroligin gene mutations in causing autism. Much research has been done into the use of a rat model to show how Borna virus infection,[17][18] exposure to valproic acid in utero,[19] and maternal immune activation[20] may cause autism.

Another goal of the use of rodent models to study autism is to identify the mechanism by which the disorder develops in humans.[1] Other researchers have developed an autism severity score to measure the degree of severity of the mice's autism, as well as the use of scent marking behavior[21] and vocalization distress[14] as models for communication.

It has been observed that mice lacking the gene for oxytocin exhibit deficits in social interaction, and that it may be possible to develop treatments for autism based on abnormalities in this and other neuropeptides.[22][23] A mutation in the CNTNAP2 gene, which has been linked to ASD in humans, results in decreased oxytocin levels in mice. Supplementing affected mice with oxytocin has been found to improve these social deficits, indicating potential therapeutic insights for improving social behaviors in this model. However, recent studies have emphasized that the majority of risk factors identified for autism do not directly connect to the oxytocin signaling pathway. This highlights that while oxytocin's role is significant, ASD is complex with a wide array of genetic influences, many of which may affect different biological pathways not directly related to oxytocin.[24]

Environmental factors

Recent advancements in research on ASD in rodent models illustrate the interaction between genetic predispositions and environmental exposures. These exposures, which span from prenatal factors such as maternal infections and diet to postnatal experiences including exposure to toxicants, insecticides, and certain[which?] medications, are increasingly recognized for their critical roles in the neuropathology of ASD.[25][26]

Specifically, a detailed analysis recognizes how these factors may heighten the susceptibility to developing ASD disrupting the neurodevelopmental process. Studies have observed an increase in immune cells of the prefrontal cortex and an augmentation of support cells in the hippocampus due to toxins in rodent models, particularly those treated with valproic acid.[25] This link between environmental exposures and distinct neurobiological alterations remains unpredictable, largely due to the variability of timing. Since environmental factors can occur at any time during the developmental process, there is much variability in the neural and behavioral phenotype of autism. Variability in environmental exposures across rodent studies may contribute to inconsistencies in observed neurodevelopmental outcomes, and therefore might develop different changes to their brain than what is expected.{{Citation needed|date=July 2025} Maternal immune activation has also been associated with increased risk for development of neurodevelopmental disorders.[27] Maternal immune activation is when inflammatory pathways are activated during pregnancy, usually by an infection. These inflammatory pathways involve the release of cytokines, or immune signaling proteins. Recent[when?] studies have shown that changes in the expression of cytokines during early stages of life are linked to the likelihood of experiencing neurodevelopmental disorders such as ASD and significant developmental delay.[2]

Injection of Poly(I:C), an immunostimulant which mimics viral infection, to pregnant rodents has been shown to induce structural brain changes and an inflammatory response in the brain of the offspring, and bring about behavioral changes such as hyperactivity, more aggressive behavior, and less social behavior in the offspring.[28] In addition to viral infection, lipopolysaccharides (LPS) has been used to mimic bacterial infection in rodents in order to observe the effects on the offspring. LPS had similar effects as Poly(I:C) on the immune system of the offspring, increasing inflammation.[29] This inflammatory state in the offspring lasted until adulthood, indicating the long-lasting effects of maternal immune activation.[29]

Genetic and phenotypic factors

There are six autism-related genes that are linked to the X chromosome.5 The first gene that has been linked to autism is the Fragile X mental retardation gene (FMR1). For example, rodents with this gene exhibit elevated cortical spine densities that are similar to those found in autism, as well as decreased social behaviors. Another gene that has been linked to autism is the methyl-CpG-binding protein type 2 gene (MECP2). In the rodent models that have MECP2 disruption, the rodents are usually normal up until the sixteenth week of age, at which point they start to develop extreme anxiety in the field, reduced nest building, and poor social interactions, which are all symptoms of autism.

The third and fourth genes that have been linked to autism are neuroligin (NLGN) 3 and 4 genes. One study found that mutations in the NLGN 3 and 4 genes lead to loss of neuroligin processing to stimulate the formation of synapses, which is a feature of autistic spectrum disorders2. The fifth and sixth genes that are linked to autism are the tuberous sclerosis genes (TSC1 and TSC2). Mutations in either of these two genes cause multiple benign tumors to grow in multiple tissues like the brain2. Lastly, many of the abnormalities found in autistic spectrum disorders involve the mTOR signaling pathway, the GABA-containing neurons, and the immune system.

Human autism spectrum disorder

All disorders have different implications when it comes to genetic makeup, both in expression and genotype, which generally impacts specific brain regions. In ASD, it is generally seen in reduced developmental growth within the brain, specifically reduced gray matter within the medial temporal lobe, which is where the amygdala and hippocampus are located. This region of the brain controls emotions and learning, which are symptomatically linked to ASD.{{Citation needed|date=July 2025} l models that establish a greater understanding of what effects these particular brain regions and genetics have on development, as well as potential measures that could be taken in order to prevent the development of the disorder in utero.3

Neuropathology of the underdeveloped synapse

Autism is caused by developmental delays that cause the brain to have lower connectivity within important[which?] regions. Alterations in the timing of critical periods in brain development have been observed in autism models, potentially impacting synaptic formation, cognitive outcomes, and the ability to create stronger synapses for basic communication and stimulus recognition.4 Furthermore, the brain's lessened development and cognitive delays are usually observable within the genetics and grey matter within the brain.3

Researchers often use rodent models to study ASD because rodent's brains are similar to humans in makeup and because they have similar social interactions and structures, allowing for social development symptoms often used to diagnose ASD to emerge. To replicate ASD, the rodents are lesioned prior to birth using prenatal valproate and compared to rodents of a control group. These rodents experience symptoms and developmental changes similar to humans with ASD. Humans with ASD are identified to have a single-gene mutation at Neuroligin-3, or NL-3 R451C.4

Neuropathology of GABA receptors

When exposed to prenatal valproate during pregnancy, the mice are born with basic deformities and the developmental delays seen symptomatically in humans.5 This is particularly advantageous and easier to study, as mice and most rodents have relatively short lifespans. This allows researchers to observe genetic factors, subtle effects, and potential interventions over a compressed time frame. As a result, they can more efficiently develop and test methods to delay the onset of the disorder, ultimately accelerating the development of new treatments for individuals with ASD. Additionally, these rodents may help trace how developmental delays occur in relation to GABA5. GABA is a neurotransmitter that is generally seen as inhibitory, but prior to birth and in early development of the brain it is often excitatory while neurons establish proper brain chemistry.

During development, there are specific times—called critical periods—where the brain is more capable of acquiring neural connections which usually leads to new behavioral and psychological skills. GABA's change from excitatory to inhibitory, as well as other neurotransmitter changes during these critical developmental stages, can impact brain development. If the critical period is early, growth can be limited, slowed, or stunted. If it is later, the brain's development is measured as complete incorrectly which may limit its ability to improve connectivity. Overall, the brain's circuitry and communication is often limited or poor within ASD, so using rodent models to study these limitations and where they come about increases researchers' understanding of the disorder and potential ways to prevent it.5

Songbird model

In 2012, a researcher from the University of Nebraska at Kearney published a study reviewing research that had been done using the zebra finch as a model for autism spectrum disorders, noting that the neurobiology of vocalization is similar between humans and songbirds and that, in both species, social learning plays a central role in the development of the ability to vocalize.[30] These parallels extend to the FOXP2 gene, expressed significantly in various parts of CNS, including areas crucial for motor functions, from embryonic development through adulthood.[31] Other research using this model has been done by Stephanie White at the University of California Los Angeles, who studied mutations in the FOXP2 gene and its potential role in learned vocalization in both songbirds (specifically the zebra finch) and humans.[32][33] Further research has elucidated how FOXP2 and its associated gene FOXP1 are distributed in language-related brain centers, influencing vocal learning through mechanisms that affect the formation of vocalization-related memories and the neural substrates of song and speech.[34] In zebra finches, knockdown of FOXP2 in the basal ganglia song nucleus Area X impairs singing, supporting the gene's role in the regulation of song production. Younger birds with knocked down FOXP1 expression have displayed selective learning deficits, impacting their ability to form memories essential for the cultural transmission of behavior, such as learning adult model songs.[34]

Controversy

In 2013, a study was published by Swiss researchers which concluded that 91% (31 out of the 34 studies reviewed) of valproic acid–autism studies using animal models had statistical flaws—specifically, they had failed to correctly use the litter as a level of statistical analysis rather than just the individual (i.e., an individual mouse or rat).[35][36]

References

  1. ↑ 1.0 1.1 Bourgeron, T.; Jamain, S. P.; Granon, S. (2006). "Animal Models of Autism: Proposed Behavioral Paradigms and Biological Studies". Transgenic and Knockout Models of Neuropsychiatric Disorders. Contemporary Clinical Neuroscience. pp. 151–174. doi:10.1007/978-1-59745-058-4_8. ISBN 978-1-58829-507-1. 
  2. ↑ 2.0 2.1 Bilbo, Staci D.; Block, Carina L.; Bolton, Jessica L.; Hanamsagar, Richa; Tran, Phuong K. (2018-01-01). "Beyond infection - Maternal immune activation by environmental factors, microglial development, and relevance for autism spectrum disorders". Experimental Neurology 299 (Pt A): 241–251. doi:10.1016/j.expneurol.2017.07.002. ISSN 0014-4886. PMID 28698032. 
  3. ↑ Callaway, E. (2011). "Rat models on the rise in autism research". Nature. doi:10.1038/nature.2011.9415. 
  4. ↑ Oddi, D.; Crusio, W. E.; d'Amato, F. R.; Pietropaolo, S. (2013). "Monogenic mouse models of social dysfunction: Implications for autism". Behavioural Brain Research 251: 75–84. doi:10.1016/j.bbr.2013.01.002. PMID 23327738. 
  5. ↑ "Vaccine Links To Autism?". 22 June 2004. https://www.cbsnews.com/news/vaccine-links-to-autism/. 
  6. ↑ Hornig, M.; Chian, D.; Lipkin, W. I. (2004). "Neurotoxic effects of postnatal thimerosal are mouse strain dependent". Molecular Psychiatry 9 (9): 833–845. doi:10.1038/sj.mp.4001529. PMID 15184908. 
  7. ↑ 7.0 7.1 Institute of Medicine (2004). Immunization Safety Review: Vaccines and Autism. Washington, DC: The National Academies Press. doi:10.17226/10997. ISBN 978-0-309-09237-1. 
  8. ↑ "Immunizations and autism: a review of the literature". Can J Neurol Sci 33 (4): 341–6. 2006. doi:10.1017/s031716710000528x. PMID 17168158. 
  9. ↑ World Health Organization (2006). "Thiomersal and vaccines: questions and answers". http://who.int/vaccine_safety/topics/thiomersal/questions/en/. 
  10. ↑ "Thimerosal in vaccines". Center for Biologics Evaluation and Research, U.S. Food and Drug Administration. 2008-06-03. https://www.fda.gov/cber/vaccine/thimerosal.htm. 
  11. ↑ Centers for Disease Control (2008-02-08). "Mercury and vaccines (thimerosal)". https://www.cdc.gov/vaccinesafety/Concerns/thimerosal/index.html. 
  12. ↑ Crawley, J. N. (2012). "Translational animal models of autism and neurodevelopmental disorders". Dialogues in Clinical Neuroscience 14 (3): 293–305. doi:10.31887/DCNS.2012.14.3/jcrawley. PMID 23226954. 
  13. ↑ Robertson, Helen. "How is a Mouse Like a Person?". The University of Chicago Neuroscience Institute. https://neuroscience.uchicago.edu/node/77. 
  14. ↑ 14.0 14.1 Klauck, S. M.; Poustka, A. (2006). "Animal models of autism". Drug Discovery Today: Disease Models 3 (4): 313–318. doi:10.1016/j.ddmod.2006.11.005. 
  15. ↑ Lewis, M.; Tanimura, Y.; Lee, L.; Bodfish, J. (2007). "Animal models of restricted repetitive behavior in autism". Behavioural Brain Research 176 (1): 66–74. doi:10.1016/j.bbr.2006.08.023. PMID 16997392. 
  16. ↑ "Science Blog | Autism Speaks". https://www.autismspeaks.org/science-blog. 
  17. ↑ Libbey, J.; Sweeten, T.; McMahon, W.; Fujinami, R. (2005). "Autistic disorder and viral infections". Journal of NeuroVirology 11 (1): 1–10. doi:10.1080/13550280590900553. PMID 15804954. 
  18. ↑ Pletnikov, M. V.; Moran, T. H.; Carbone, K. M. (2002). "Borna disease virus infection of the neonatal rat: Developmental brain injury model of autism spectrum disorders". Frontiers in Bioscience 7 (1–3): d593–d607. doi:10.2741/pletnik. PMID 11861216. 
  19. ↑ Roullet, F. I.; Lai, J. K. Y.; Foster, J. A. (2013). "In utero exposure to valproic acid and autism — A current review of clinical and animal studies". Neurotoxicology and Teratology 36: 47–56. doi:10.1016/j.ntt.2013.01.004. PMID 23395807. Bibcode: 2013NTxT...36...47R. 
  20. ↑ Parker-Athill, E. C.; Tan, J. (2010). "Maternal Immune Activation and Autism Spectrum Disorder: Interleukin-6 Signaling as a Key Mechanistic Pathway". Neurosignals 18 (2): 113–128. doi:10.1159/000319828. PMID 20924155. 
  21. ↑ Wöhr, M.; Scattoni, M. L. (2013). "Behavioural methods used in rodent models of autism spectrum disorders: Current standards and new developments". Behavioural Brain Research 251: 5–17. doi:10.1016/j.bbr.2013.05.047. PMID 23769995. 
  22. ↑ Lim, M. M.; Bielsky, I. F.; Young, L. J. (2005). "Neuropeptides and the social brain: Potential rodent models of autism". International Journal of Developmental Neuroscience 23 (2–3): 235–243. doi:10.1016/j.ijdevneu.2004.05.006. PMID 15749248. 
  23. ↑ Chadman, K. K.; Guariglia, S. R.; Yoo, J. H. (2012). "New directions in the treatment of autism spectrum disorders from animal model research". Expert Opinion on Drug Discovery 7 (5): 407–416. doi:10.1517/17460441.2012.678828. PMID 22494457. 
  24. ↑ Hörnberg, Hanna; Pérez-Garci, Enrique; Schreiner, Dietmar; Hatstatt-Burklé, Laetitia; Magara, Fulvio; Baudouin, Stephane; Matter, Alex; Nacro, Kassoum et al. (August 2020). "Rescue of oxytocin response and social behaviour in a mouse model of autism" (in en). Nature 584 (7820): 252–256. doi:10.1038/s41586-020-2563-7. ISSN 1476-4687. PMID 32760004. Bibcode: 2020Natur.584..252H. 
  25. ↑ 25.0 25.1 Wang, Ling; Wang, Binquan; Wu, Chunyan; Wang, Jie; Sun, Mingkuan (January 2023). "Autism Spectrum Disorder: Neurodevelopmental Risk Factors, Biological Mechanism, and Precision Therapy" (in en). International Journal of Molecular Sciences 24 (3): 1819. doi:10.3390/ijms24031819. ISSN 1422-0067. PMID 36768153. 
  26. ↑ Pensado-López, Alba; Veiga-Rúa, Sara; Carracedo, Ángel; Allegue, Catarina; Sánchez, Laura (November 2020). "Experimental Models to Study Autism Spectrum Disorders: hiPSCs, Rodents and Zebrafish" (in en). Genes 11 (11): 1376. doi:10.3390/genes11111376. ISSN 2073-4425. PMID 33233737. 
  27. ↑ Haddad, Faraj L.; Patel, Salonee V.; Schmid, Susanne (June 2020). "Maternal Immune Activation by Poly I:C as a preclinical Model for Neurodevelopmental Disorders: A focus on Autism and Schizophrenia". Neuroscience and Biobehavioral Reviews 113: 546–567. doi:10.1016/j.neubiorev.2020.04.012. ISSN 1873-7528. PMID 32320814. https://zenodo.org/record/7884474. 
  28. ↑ Goh, Jen-Yin; O'Sullivan, Saoirse E.; Shortall, Sinead E.; Zordan, Nicole; Piccinini, Anna M.; Potter, Harry G.; Fone, Kevin C.F.; King, Madeleine V. (2020-10-01). "Gestational poly(I:C) attenuates, not exacerbates, the behavioral, cytokine and mTOR changes caused by isolation rearing in a rat 'dual-hit' model for neurodevelopmental disorders" (in en). Brain, Behavior, and Immunity 89: 100–117. doi:10.1016/j.bbi.2020.05.076. ISSN 0889-1591. PMID 32485291. https://www.sciencedirect.com/science/article/abs/pii/S0889159120300763. 
  29. ↑ 29.0 29.1 Talukdar, Pinku Mani; Abdul, Fazal; Maes, Michael; Binu, V. S.; Venkatasubramanian, Ganesan; Kutty, Bindu M.; Debnath, Monojit (October 2020). "Maternal Immune Activation Causes Schizophrenia-like Behaviors in the Offspring through Activation of Immune-Inflammatory, Oxidative and Apoptotic Pathways, and Lowered Antioxidant Defenses and Neuroprotection". Molecular Neurobiology 57 (10): 4345–4361. doi:10.1007/s12035-020-02028-8. ISSN 1559-1182. PMID 32720073. 
  30. ↑ Panaitof, S. C. (2012). "A songbird animal model for dissecting the genetic bases of autism spectrum disorder". Disease Markers 33 (5): 241–249. doi:10.1155/2012/727058. PMID 22960335. 
  31. ↑ Lüffe, Teresa M.; D'Orazio, Andrea; Bauer, Moritz; Gioga, Zoi; Schoeffler, Victoria; Lesch, Klaus-Peter; Romanos, Marcel; Drepper, Carsten et al. (2021-10-14). "Increased locomotor activity via regulation of GABAergic signalling in foxp2 mutant zebrafish—implications for neurodevelopmental disorders" (in en). Translational Psychiatry 11 (1): 529. doi:10.1038/s41398-021-01651-w. ISSN 2158-3188. PMID 34650032. 
  32. ↑ "Finding an Animal Model for Language Development". 25 July 2012. http://www.autismspeaks.org/news/news-item/finding-animal-model-language-development. 
  33. ↑ Condro, M. C.; White, S. A. (2014). "Distribution of language-related Cntnap2 protein in neural circuits critical for vocal learning". Journal of Comparative Neurology 522 (1): 169–185. doi:10.1002/cne.23394. PMID 23818387. 
  34. ↑ 34.0 34.1 Csillag, András; Ádám, Ágota; Zachar, Gergely (2022). "Avian models for brain mechanisms underlying altered social behavior in autism". Frontiers in Physiology 13. doi:10.3389/fphys.2022.1032046. ISSN 1664-042X. PMID 36388132. 
  35. ↑ Lazic, S. E.; Essioux, L. (2013). "Improving basic and translational science by accounting for litter-to-litter variation in animal models". BMC Neuroscience 14. doi:10.1186/1471-2202-14-37. PMID 23522086. 
  36. ↑ Varughese, Ansa (2 April 2013). "New Study Says 91% Of Autism Studies Using Certain Animal Models Are Statistically Flawed". Medical Daily. http://www.medicaldaily.com/new-study-says-91-autism-studies-using-certain-animal-models-are-statistically-flawed-244865. 

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