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Summary of non-human primate models of autism

2021-03-11
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In the past few decades, rodents have been widely used to study the pathogenesis of ASD. However, there are major evolutionary differences between rodents and humans in social behavior and brain anatomy. To this end, in addition to rodent models of autism (summary from the previous issue: [Collection] three thousand words to summarize commonly used rodent models for autism research), researchers have tried to establish some non-human primate models to promote ASD research.

preclinical models of ASD
Source: Bauman MD, Schumann CM. Advances in nonhuman primate models of autism: Integrating neuroscience and behavior. Exp Neurol. 2018;299(Pt A):252-265. doi:10.1016/j.expneurol.2017.07.021

1. Genetic model

Although there are currently a large number of genetically modified mouse models targeting ASD-related genes, there is still little understanding of how specific gene mutations can lead to a series of molecular abnormalities, changes in neural circuits, and ultimately changes in behavior. The latest advances in genetic modification tools have also made it possible to explore genetic risk factors for ASD in species that are more closely related to humans. Genes related to ASD, such as MECP2 and SHANK3, have been targeted to produce non-human primate models of ASD.

Methyl CpG binding protein 2 (MeCP2) plays a key role in transcriptional regulation and microRNA processing. Mutations in the MECP2 gene are found in 90% of patients with Rett syndrome. Rett syndrome is a serious developmental disorder with autistic phenotype.

Based on the strategy of lentiviral infection, Qiu Zilong and Sun Qiang, from the Shanghai Institute of Neuroscience, Chinese Academy of Sciences, constructed transgenic cynomolgus monkeys (Macaca fascicularis) that overexpress human MeCP2 in the brain. These transgenic monkeys exhibit increased frequency of repetitive cyclical movements and increased anxiety. , ASD-like behaviors such as reduced social interaction and relatively weak cognition, and exhibit stable genetic genetic inheritance.

Heterozygous SHANK3 mutations and deletions are one of the most common genetic mutations in ASD. SHANK3 mutant macaques induced by CRISPR/Cas9 showed obvious sleep disorders, motor deficits, increased repetitive behaviors, social and learning disorders, etc., which are closer to ASD-like behaviors and neurological phenotypes than rodent models.

2. Environmental model

Recent evidence indicates that the prenatal environment, especially the immune environment of the mother and the fetus, may be a promising field in the etiology of ASD.

In the middle and late stages of pregnancy, IgG isotype antibodies from the mother are transported through the placenta to protect the immature fetus with the immune system. However, in addition to immunoprotective antibodies, autoantibodies that react to fetal “self” proteins can also pass through the placenta, leading to potential neonatal autoimmune diseases.

The recently discovered protein targets of these antibodies play a key role in neurodevelopment, supporting the hypothesis that prenatal exposure to anti-brain autoantibodies may disrupt brain development trajectories and ultimately lead to autism. A study found that when rhesus monkeys were exposed to specific ASD-related maternal antibodies before giving birth, their offspring showed inappropriate social styles with new animals, as well as social interactions with familiar peers. defect.

Modeling autism in non-human primates
Source: Zhao H, Jiang YH, Zhang YQ. Modeling autism in non-human primates: Opportunities and challenges. Autism Res. 2018;11(5):686-694. doi:10.1002/aur.1945

Maternal infections during pregnancy are associated with an increased risk of autism in the offspring. This correlation is well confirmed by experiments that activating the maternal immune system in rodents during pregnancy will produce offspring with abnormal brain and behavioral development. To bridge the gap between the clinical population and the rodent model of maternal immune activation (MIA), researchers have developed a non-human primate model of MIA. The offspring of pregnant rhesus monkeys injected with poly IC during pregnancy have abnormal motor stereotypes and repetitive behaviors, as well as abnormal social interactions.

3. Phenotype identification of non-human primate ASD model

Similar to disease models of other species, the phenotypic analysis of non-human primate ASD models usually includes biochemistry, molecular, cellular, behavioral analysis, and brain imaging.

Monkey behavior analysis is usually performed by scoring video-recorded behavioral data in natural and designed experimental environments. Behaviors that are frequently checked include positive social contact, such as grooming and sitting together, environmental exploration, aggressive behavior, and stereotyped behavior. Stereotyped behaviors are repetitive and involuntary movements, such as clapping hands, body shaking, and head shaking.

The eye tracer assay can be used to assess the activity of the neural circuits in the brains of non-human primates. Visual attention is the ability to focus on the relevant aspects of the visual world while ignoring the distracting aspects. Abnormal eye expression is considered to be one of the key features of ASD. In a manner similar to humans, non-human primates can measure social information processing and facial expression recognition to a certain extent through eye tracking systems, which is not suitable for rodents. Non-invasive electroencephalogram (EEG) can be used to record the network activity of cortical neurons in freely moving monkeys.

Brain imaging, such as MRI/fMRI and diffusion tensor imaging (DTI), is commonly used to analyze brain structures and for longitudinal follow-up studies in humans. Functional magnetic resonance imaging (fMRI) is often used to assess changes in brain activity when performing specific tasks. A method for longitudinal assessment of normal brain growth patterns using MRI has been reported in monkeys.

The use of MRI to study the brain structure of ASD patients also found that brain development in early childhood is abnormal. MECP2-deficient monkeys exhibit abnormal brain development, including reduced gray matter volume and cortical thickness in specific brain regions.

references:

1. Wolfgang MJ, Golos TG. Nonhuman primate transgenesis: progress and prospects. Trends Biotechnol. 2002;20(11):479-484. doi:10.1016/s0167-7799(02)02052-8

2.Bauman MD, Schumann CM. Advances in nonhuman primate models of autism: Integrating neuroscience and behavior. Exp Neurol. 2018;299(Pt A):252-265. doi:10.1016/j.expneurol.2017.07.021

3.Liu Z, Li X, Zhang JT, et al. Autism-like behaviours and germline transmission in transgenic monkeys overexpressing MeCP2. Nature. 2016;530(7588):98-102. doi:10.1038/nature16533

4.Bauman MD, Iosif AM, Ashwood P, et al. Maternal antibodies from mothers of children with autism alter brain growth and social behavior development in the rhesus monkey. Transl Psychiatry. 2013;3(7):e278. Published 2013 Jul 9 . doi:10.1038/tp.2013.47

5.Rose DR, Careaga M, Van de Water J, McAllister K, Bauman MD, Ashwood P. Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation. Brain Behav Immun. 2017;63 :60-70. doi:10.1016/j.bbi.2016.11.020

6.Zhao H, Jiang YH, Zhang YQ. Modeling autism in non-human primates: Opportunities and challenges. Autism Res. 2018;11(5):686-694. doi:10.1002/aur.1945

7. Li Shen, Wu Haitao. Research progress in experimental animal models of autism spectrum disorder[J].Chinese Journal of Pharmacology and Toxicology,2020,34(02):133-141.

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