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The development of an animal model of autism is one approach researchers use to study potential causes of autism. [1] Given the complexity of autism and its etiology, researchers often focus only on single features of autism when using animal models. [2]
One of the more common rodent models is the Norway rat (Rattus norvegicus). [3] More recent research has used the house mouse ( Mus musculus ) to model autism because it is a social species. Other strains of mice used include mu opioid receptor knockout mice, as well as Fmr1 knockout mice; the latter are also used as animal models of Fragile X syndrome. [4]
The Norway rat has been used, for example, by Mady Hornig to implicate thiomersal in autism. [5] [6] The current scientific consensus is that no convincing scientific evidence supports these claims, [7] [8] and major scientific and medical bodies such as the Institute of Medicine [7] and World Health Organization [9] (WHO) as well as governmental agencies such as the U.S. Food and Drug Administration [10] (FDA) and Centers for Disease Control and Prevention [11] (CDC) 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 autism 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 human, 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 of ASD
Looking at the environmental factors of autistic spectrum disorder in rodents helps us to understand the neuropathology of the disorder which can be compared to humans. Environmental factors have been studied in animal rodent models and have been seen to influence brain development and play a role in gene expression. Recent advancements in research on ASD in rodent models illustrate that 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 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 (VPA). [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. The environment can cause unknown changes in brain development of rodents because they don't all live in the same habitat and therefore might develop different changes to their brain than what is expected.
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 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 autism spectrum disorder (ASD) and significant developmental delay. [2] Injection of Poly(I:C), which is an immunostimulant and mimics viral infection, to pregnant rodents has been shown to induce an inflammatory response in the brain of the offspring, induce structural brain changes in 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] Overall, recent studies make a case for infection during pregnancy being an environmental risk factor for neurodevelopmental disorders such as ASD or schizophrenia in rodents.
Genetic and Phenotypic Factors of ASD
There have been six autism-related genes that are linked to the X chromosome when it comes to autistic spectrum disorder.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 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 and then they start to develop extreme anxiety in the field, reduced nest building, and poor social interactions which are all symptoms of autism1. 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 one 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
Understanding human neurodevelopmental disorders often requires adequate models to understand the overall nature of the disorder and the general impacts the disorder makes on the brain itself. Naturally each disorder has different implications when it comes to genetic makeup, phenotypically and genotypically, and generally this impacts particular brain regions. In Autism Spectrum Disorder (ASD) it is generally seen in reduced developmental growth within the brain, and more specifically reduced gray matter within the medial temporal lobe (MTL), which is where the amygdala and hippocampus are located. This is critical in understanding Autism because this region of the brain controls emotions and learning, which is symptomatically linked to ASD. In addition, this supports the need for animal models that establish a greater understanding of what effects these particular brain regions and genetics have on development, and if there are measures we can take to prevent the onset of the disorder3.
Neuropathology of the Underdeveloped Synapse
Autism Spectrum Disorder (ASD) is caused by developmental delays that cause the brain to have lower connectivity within particularly important regions. The synapses within the brain have critical importance in development in young children, especially during their critical period. Autistic brains often have delayed or early critical periods, causing complications within the brain's developmental stages and ability to create stronger synapses for basic communication and stimulus recognition4. Furthermore, the brain's lessened development and cognitive delays are usually observable within the genetics and grey matter within the brain3.
Rodent models have been established as good examples because their brains are akin to humans in makeup. Additionally, they have similar social interactions and relationships that humans have, which shows the social development symptoms often used to diagnose ASD. Rodents when used as models are compared to their normal developed brains, but to replicate ASD, the rodents are lesioned prior to birth using prenatal valproate (VPA). The rodents then experience similar symptoms and developmental changes that occur with human's with ASD. Human's with ASD are identified to have a single-gene mutation at Neuroligin-3, or NL-3 R451C. These particularly simple changes to the rodents and human brains impact them greatly in their ability to develop properly4.
Neuropathology of GABA Receptors
Rodents, most especially mice, are excellent animal models of autism because they have similar social relationships and neuroscience. When exposed to prenatal valproate (VPA) during pregnancy, the mice are born with basic deformities and the developmental delays seen symptomatically in humans5. This is all comparable and easier to study since the lifespan of mice and most rodents is shorter, so being able to understand the genetics, minute effects, and test methods to reduce the onset of the disorder allows for researchers to develop new treatment methods quickly and effectively to help humans on the spectrum. Additionally, these rodents may trace back particular models to how the 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 the development the brain goes through. If the critical period is early, growth can be limited, slowed, or even stunted early on. Additionally, 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 it5.
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]
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]
Asperger syndrome (AS), also known as Asperger's syndrome, formerly described a neurodevelopmental disorder characterized by significant difficulties in social interaction and nonverbal communication, along with restricted and repetitive patterns of behavior, interests, and activities. The syndrome has been merged with other disorders into autism spectrum disorder (ASD) and is no longer considered a stand-alone diagnosis. It was considered milder than other diagnoses that were merged into ASD due to relatively unimpaired spoken language and intelligence.
Forkhead box protein P2 (FOXP2) is a protein that, in humans, is encoded by the FOXP2 gene. FOXP2 is a member of the forkhead box family of transcription factors, proteins that regulate gene expression by binding to DNA. It is expressed in the brain, heart, lungs and digestive system.
Developmental disorders comprise a group of psychiatric conditions originating in childhood that involve serious impairment in different areas. There are several ways of using this term. The most narrow concept is used in the category "Specific Disorders of Psychological Development" in the ICD-10. These disorders comprise developmental language disorder, learning disorders, motor disorders, and autism spectrum disorders. In broader definitions ADHD is included, and the term used is neurodevelopmental disorders. Yet others include antisocial behavior and schizophrenia that begins in childhood and continues through life. However, these two latter conditions are not as stable as the other developmental disorders, and there is not the same evidence of a shared genetic liability.
Autism spectrum disorders (ASD) are neurodevelopmental disorders that begin in early childhood, persist throughout adulthood, and affect three crucial areas of development: communication, social interaction and restricted patterns of behavior. There are many conditions comorbid to autism spectrum disorders such as attention-deficit hyperactivity disorder and epilepsy.
Neurodevelopmental disorders are a group of conditions that begin to emerge during childhood. According to the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (DSM-5) published in 2013, these conditions generally appear in early childhood, usually before children start school, and can persist into adulthood. The key characteristic of all these disorders is that they negatively impact a person's functioning in one or more domains of life depending on the disorder and deficits it has caused. All of these disorders and their levels of impairment exist on a spectrum, and affected individuals can experience varying degrees of symptoms and deficits, despite having the same diagnosis.
The heritability of autism is the proportion of differences in expression of autism that can be explained by genetic variation; if the heritability of a condition is high, then the condition is considered to be primarily genetic. Autism has a strong genetic basis. Although the genetics of autism are complex, autism spectrum disorder (ASD) is explained more by multigene effects than by rare mutations with large effects.
Many causes of autism, including environmental and genetic factors, have been recognized or proposed, but understanding of the theory of causation of autism is incomplete. Attempts have been made to incorporate the known genetic and environmental causes into a comprehensive causative framework. ASD is a neurodevelopmental disorder marked by impairments in communicative ability and social interaction and restricted/repetitive behaviors, interests, or activities not suitable for the individual's developmental stage. The severity of symptoms and functional impairment vary between individuals.
Autism therapies include a wide variety of therapies that help people with autism, or their families. Such methods of therapy seek to aid autistic people in dealing with difficulties and increase their functional independence.
Mady Hornig is an American psychiatrist and an associate professor of epidemiology at Columbia University's Mailman School of Public Health. A physician-scientist, her research involves clinical, epidemiological, and animal model research on autism and related neurodevelopmental conditions. She directs the clinical core of an international investigation of the role of Borna disease virus in human mental illness and participates as a key investigator for the Autism Birth Cohort (ABC) project, a large prospective epidemiological study, based in Norway, that is identifying how genes and timing interact with environmental agents preceding the onset of autism spectrum diagnoses. In 2006, she was appointed as guest professor at the school of basic medical science of Beijing University in Beijing, China.
Neurogenomics is the study of how the genome of an organism influences the development and function of its nervous system. This field intends to unite functional genomics and neurobiology in order to understand the nervous system as a whole from a genomic perspective.
Autism, formally called autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental disorder marked by deficits in reciprocal social communication and the presence of restricted and repetitive patterns of behavior. Other common signs include difficulties with social interaction, verbal and nonverbal communication, along with perseverative interests, stereotypic body movements, rigid routines, and hyper- or hyporeactivity to sensory input. Autism is clinically regarded as a spectrum disorder, meaning that it can manifest very differently in each person. For example, some are nonspeaking, while others have proficient spoken language. Because of this, there is wide variation in the support needs of people across the autism spectrum.
The imprinted brain hypothesis is an unsubstantiated hypothesis in evolutionary psychology regarding the causes of autism spectrum and schizophrenia spectrum disorders, first presented by Bernard Crespi and Christopher Badcock in 2008. It claims that certain autistic and schizotypal traits are opposites, and that this implies the etiology of the two conditions must be at odds.
Autism spectrum disorder (ASD) refers to a variety of conditions typically identified by challenges with social skills, communication, speech, and repetitive sensory-motor behaviors. The 11th International Classification of Diseases (ICD-11), released in January 2021, characterizes ASD by the associated deficits in the ability to initiate and sustain two-way social communication and restricted or repetitive behavior unusual for the individual's age or situation. Although linked with early childhood, the symptoms can appear later as well. Symptoms can be detected before the age of two and experienced practitioners can give a reliable diagnosis by that age. However, official diagnosis may not occur until much older, even well into adulthood. There is a large degree of variation in how much support a person with ASD needs in day-to-day life. This can be classified by a further diagnosis of ASD level 1, level 2, or level 3. Of these, ASD level 3 describes people requiring very substantial support and who experience more severe symptoms. ASD-related deficits in nonverbal and verbal social skills can result in impediments in personal, family, social, educational, and occupational situations. This disorder tends to have a strong correlation with genetics along with other factors. More research is identifying ways in which epigenetics is linked to autism. Epigenetics generally refers to the ways in which chromatin structure is altered to affect gene expression. Mechanisms such as cytosine regulation and post-translational modifications of histones. Of the 215 genes contributing, to some extent in ASD, 42 have been found to be involved in epigenetic modification of gene expression. Some examples of ASD signs are specific or repeated behaviors, enhanced sensitivity to materials, being upset by changes in routine, appearing to show reduced interest in others, avoiding eye contact and limitations in social situations, as well as verbal communication. When social interaction becomes more important, some whose condition might have been overlooked suffer social and other exclusion and are more likely to have coexisting mental and physical conditions. Long-term problems include difficulties in daily living such as managing schedules, hypersensitivities, initiating and sustaining relationships, and maintaining jobs.
Translational neuroscience is the field of study which applies neuroscience research to translate or develop into clinical applications and novel therapies for nervous system disorders. The field encompasses areas such as deep brain stimulation, brain machine interfaces, neurorehabilitation and the development of devices for the sensory nervous system such as the use of auditory implants, retinal implants, and electronic skins.
Sex and gender differences in autism exist regarding prevalence, presentation, and diagnosis.
Autism is characterized by the early onset of impairments in reciprocal social interaction and communication and restricted repetitive behaviors or interests. One of the many hypotheses explaining the psychopathology of autism, the deficit in joint attention hypothesis is prominent in explaining the disorder's social and communicative deficits. Nonverbal autism is a subset of autism spectrum where the person does not learn how to speak. One study has shown that 64% of autistic children who are nonverbal at age 5, are still nonverbal 10 years later.
The mechanisms of autism are the molecular and cellular processes believed to cause or contribute to the symptoms of autism. Multiple processes are hypothesized to explain different autism spectrum features. These hypotheses include defects in synapse structure and function, reduced synaptic plasticity, disrupted neural circuit function, gut–brain axis dyshomeostasis, neuroinflammation, and altered brain structure or connectivity.
Gloria Choi is an American neuroscientist and neuroimmunologist and the Samuel A. Goldblith Career Development Professor in the Picower Institute for Learning and Memory at the Massachusetts Institute of Technology. Choi is known for elucidating the role of the immune system in the development of autism spectrum disorder-like phenotypes. Her lab currently explores how sensory experiences drive internal states and behavioural outcomes through probing the olfactory system as well as the neuroimmune system.
The pathophysiology of autism is the study of the physiological processes that cause or are otherwise associated with autism spectrum disorders.
Yehezkel Ben-Ari is a neurobiologist specializing in brain development and the development of brain disorders. He has made seminal contributions to the understanding of brain activity in health and disease and notably autism, epilepsies and related infantile disorders.
