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Introduction
The human body may be regarded as a set of interconnected systems that affect each other. For instance, a bidirectional link between the immune system and the nervous system forms neuroimmune interactions, while the nature of synapses between a neuron and an immune cell is explored insufficiently (1). Among gastrointestinal tract (GIT) health issues related to autism, it is possible to enumerate abdominal pain, vomiting, bloating, and other conditions that are caused by neuroinflammation and gut microbiota responses (4). The gastrointestinal and immune dysfunctions as well as clinical changes in synapses in terms of autism will be studied in this paper to distinguish between neuroimmune changes in the gut-brain axis to characterize ASD-associated mutations.
Autism Spectrum Disorder (ASD)
ASD is a spectrum of psychological characteristics that illustrate a wide range of abnormal behavior and difficulties in social interaction, as well as severely limited interests and recurring behavioral acts. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) elaborated by the American Psychiatric Association (APA), the following conditions are included in ASD: autism (Kanner’s syndrome), Asperger’s syndrome, childhood disintegrative disorder (CDD), and pervasive developmental disorder not otherwise specified (PDD-NOS) (10).
As a rule, ASD begins in childhood yet persists in adolescence and adulthood. In most cases, these conditions manifest themselves in the first 5 years of life (6). 1 out of 160 children suffers from ASD, while this estimate is an averaged figure, and the reported prevalence varies considerably between studies – in some well-controlled researches, much larger numbers are reported (6, 7, 48). It should be emphasized that little is known about the prevalence of ASD in low- and middle-income countries. Based on the epidemiological studies conducted over the past 50 years, the prevalence of ASD appears to be increasing throughout the world (26-28). There are many possible explanations for such an increase, including the expansion of diagnostic criteria and reporting tools.
The available epidemiological data unequivocally indicate the absence of a causal link between ASD and the vaccine against measles, mumps, and rubella. It was discovered that previous studies pointing to the existence of such an association had methodological flaws (8). Similarly, there is no evidence that any childhood vaccine can increase the risk of autism spectrum disorders (8, 25). In contrast, reviews of evidence for a potential connection between the thiomersal preservative and aluminum adjuvants in the inactivated vaccine and the risk of autism spectrum disorders strongly suggest that there is no risk. ASD includes three groups of symptoms associated with qualitative disorders of social reciprocity, communication, perceptual disorders, and stereotyped behaviors. Stable deficits in social communication and social interaction in different contexts that exist currently or may be noted in one’s history as well as limitedness and repeatability in the structure of behavior compose the key symptoms (9). These symptoms cause a clinically important impairment in occupational, social, and other significant spheres of a person’s daily functioning.
Gastrointestinal Dysfunction in ASD
The core co-morbidity associated with ASD in children is presented by gastrointestinal complications (GI) expressed in neural and neuron responses from gut microbiota (2). The latter influences the formation of the immune response of a child’s body, especially during the transient immunological failure period that is characteristic of children of the first years of life (1). Therefore, one may assume that the more diverse a child’s intestinal microbiota, the more healthy he or she will grow.
Taking into account that children suffering from serious viral infections often have the autistic disorder, researchers reproduced this situation in mice (9). Scientists caused an immune response in rodent females by administering a drug that mimics the function of the virus, after which mice with symptoms of ASD were born. The researchers noticed that autistic mice also showed the symptoms of GIT problems, which indicated anomalies in the development of microflora (2, 3, 9). Moreover, the digestive tract of rodents was also affected: harmful substances and bacteria penetrated through the walls of the stomach and intestines into the bloodstream. To make sure that the autistic behavior of mice is affected by digestive disorders, the scholars injected the bacterium Bacteroides fragilis into the rodents, which is used in the experimental treatment of diseases of the stomach and intestines in animals (3-5). As a result of the study, the treatment has affected, and intestinal permeability has decreased.
Immune Dysfunction in ASD
The presence of conditionally pathogenic flora in the intestine not only contributes to the stimulation of the immune system but, in several cases, it is accompanied by the appearance of signs of inflammation in the intestinal mucosa. In this connection, the following question often arises: is inflammation in the bowel a reflection of the adaptive physiological process, or is it the evidence of a disruption in the adaptation and mucosal damage, thus being pathological? (11, 14). One of the possible levels of inflammation in the intestines can be the level of calprotectin in the feces. Calprotectin is a protein that reflects the degree of granulocyte infiltration of the mucosa that is characteristic of inflammation. The recent study that focused on the level of calprotectin in healthy full-term and preterm infants showed an elevated level of this protein with necrotic enterocolitis, infections, allergies, autoimmune enteropathy, and decreased level (32). The test subjects with congenital anomalies of enterocytes were also noted.
Clinical mutations affecting synaptic function
A range of specific mutations is characteristic of subjects with autism. With the help of genetic analyses and the study of pedigrees, it was possible to identify 6 genes associated with the symptoms of ASD (26, 27). The identified genes regulate the development of inter-neuron contacts (synapses) and affect the transmembrane potential, and dysfunction of these genes disrupts the development of the brain and reduces the ability to learn (27). It was revealed that if mutant versions of these genes are obtained by the child from both parents, the risks increase. One of them (c3orf58) was absent in autistics in terms of homozygous deletion. The other five genes – NHE9, PCDH10, contactin-3, RNF8, and SCN7A were present in autistic individuals, but the work of these genes was impaired due to mutations.
The expression of these genes refers to the excitation of neurons and the depolarization of cell membranes. In another study, the authors noted that, first of all, a range of genes playing a role in the development of the brain tend to change (28). For example, scholars identified an ablation in one of the genes called stargazin, which is necessary to regulate signaling between neurons in the brain (28). It is known that when a neuron is excited, a set of transcription factors is developed that include or suppress the work of genes that control the development and plasticity of synapses.
Shank 3 mutations
Among the strong mutations, there is a change in the gene called Shank3 – the one that is rather widespread in people with autism. In particular, 0.5 percent of people with these disorders have a mutation in the Shank 3 gene (12). Scientists determined that Shank3 assists cells in responding to input from other neurons, but there are two other Shank genes, and all three can fill the space reserved for each other so that it is difficult to pinpoint exactly what the proteins from the Shank group do (13; 49, 50). Mice with a mutant version of Shank 3 inherent to autistic people – InsG3680 – reproduced the behavior characteristic of autistic people: they did not socialize, slowly trained, performed stereotyped actions, and showed a high degree of anxiety when responding to a new situation compared to the control groups of mice (16, 19). It is assumed that the shortened, missing part of the peptide segment in schizophreniform mice may be responsible for social insufficiency at the mature stages of the development of both mice and humans.
The researchers also found that the loss of Shank 3 affects a known set of proteins that will include the signal protein Wnt (29). When Wnt binds to a receptor on a cell, it initiates a series of interactions that affect the connection of different genes that, in turn, contribute to the emergence of many cellular processes, including embryonic development, tissue regeneration, and tumor formation. According to the researchers, the Wnt and Shank family can be included in the progress of autism independently, but the fact that they can interact indicates how these genes act in cooperation, and their violation causes the development of brain damage. The discovery provides the opportunity for finding the treatment of autism with drugs that promote the establishment of Wnt signaling in case a patient has autism caused by a mutation of the specified gene.
Neuroligin-3 mutations
The experiments in mice demonstrate that the inability of normal social interaction is associated with a dysfunction of the dopaminergic neurons in the ventral area – the part of the brain’s reward system (30). Antisocial behavior also exhibited mice with a mutation of the NLGN3 gene involved in dopamine production. To test how the behavior of mice changes, if the activity of their brain is altered, the scholars inhibited the dopaminergic neurons of the central area of the tire by injecting an artificial receptor selectively activated only with artificial drugs (DREADD) (15). Mice with a deficiency of neuroligin-3 on average 40 seconds less interacted with relatives and spent twice as much time to inspect new premises than mice without the mutation (15). Scientists, therefore, conclude that the disturbed activity of dopaminergic neurons in the central area, which is part of the brain’s reward system, is associated with a violation of social interaction and greater preferences for new objects and subjects.
The authors of another study discovered that normal, unmodified mice that lived with autistic mice lost interest in each other (31). The seedling of normal and modified mice, the researchers noticed that healthy animals again had a social interest in their comrades. More to the point, if mice in which the Neuroligin-3 gene mutation was turned off, it was turned on again, then in both of them and their unmodified neighbors in the cell, the autistic symptoms in behavior disappeared. In other words, the situation looked as if antisocial mice infected others with their asociality.
Genetic mouse models of ASD
Since mice and humans have approximately 85 percent of similarly coded genes, the former can be used as a model for studying how genetic mutations affect brain development (33-35). The fact is that changes in mouse DNA mimic those in human DNA and vice versa. Also, mice demonstrate behavior that can be used as models for studying human behavior. Further consideration of specific gene mutations is beneficial to understand their role in ASD.
Shank3 KO mice
Several types of research affected postsynaptic proteins, including SAPAP3 and Shank3 in the pathogenesis of neural disorders such as ASD, obsessive-compulsive disorders, and bipolar disorder (BD) (20-23). The gene-binding protein 2 (nArgBP2) related to neuron-Abelson was initially determined as a protein that communicates with Shank3 and SAPAP3. The recent research illustrates that the genetic removal of nArgBP2 in mice causes manic/bipolar behavior reminiscent of BD symptoms (23). Nevertheless, the role of nArgBP2 in the synapse or its association with synaptic dysfunctions remains unexplored. These findings provide conclusive evidence that nArgBP2 controls spinal morphogenesis based on the establishment of the Rac1 / WAVE / PAK / cofilin pathway (36). It is also important to note that Shank3 knockout causes a stable and selective inhibition of the generation of an exciting synapse, controlling the dynamics of actin.
Neuroligin-3R451C-mice
The increased cortical exhibition is noted in mice with autism-related Neuroligin-3R451C. The replication of amino acid 451 (R451C) by Neuroligin 3 (NLGN3R451C) is a potential cause of autism, as suggested by scholars who experimented with genetic mutations in mice (37, 38). The somatosensory cortex of these mice is characterized by inhibitory synaptic strength, which resulted in imbalance and spontaneous mIPSCs in Nlgn3R451C mice. At the same time, no change in PV and SOM interneurons density was detected, which means the potentially improved synaptic transmission that was also associated with endocannabinoid signaling.
Enteric Nervous System
Since the enteric nervous system (ENS) contains a large number of neurons comparable to those in the central nervous system (CNS), the digestive tract is recognized as the largest lymphatic organ in the human body. When external antigens gain access to the intestinal mucosa, the immune-neuronal signaling triggers the stereotyped behavior of propulsive contractions (39). This activity leads to the abundant secretion of water, electrolytes, and mucus, as well as to the increased motor activity, which is clinically manifested by spastic pain in the abdomen, urges for defecation, and watery diarrhea (40). As described earlier, along the entire length of the intestine, there are many immune cells, each of which is anatomically linked to the elements of ENS. The latter synchronously interact with the immune system to provide one of the first lines of defense against the external antigens. It is known that the inflammatory mediators produced by mast cells cause the excitation of EN), which, in turn, causes propulsive contractions (39, 40). The key mediators of the mast cell-ENS connection are histamine, 5-hydroxytryptamine, adenosine, interleukins, leukotrienes, prostaglandins, and mast cell proteases.
People with autism are prone to problems with digestion, which have the same genetic markers of mutations damaging the neurons of the brain. Although scholars are only at the very beginning of understanding the interaction between the brain and gastrointestinal system, the so-called second brain already highlights the mechanisms of pathologies developed in the main brain (17, 18). Theoretically, it is possible to utilize a biopsy of the intestinal nerve tissue for early diagnosis and also evaluate the effectiveness of the treatment. The cells of ENS can even be used to treat its neurodegenerative diseases. The experimental transplantation of stem neurons into the brain is known to replace dead cells (18, 19, 24, 41, 42). Furthermore, the cultivation of the mentioned cells from the spinal cord or the brain is complicated, yet stem nerve cells in the gastrointestinal plexus in adults have already been detected.
Neuro-Immune System Interactions
The immune system (IS) is associated with the nervous system (NS) in two ways: through the autonomic NA and neuroendocrine, mainly, through its pituitary mechanisms of the latter (43). This connection is established with the help of biologically active molecules that fail to communicate with the cells of the IS through chemically specialized nerve fibers that are present in the primary and secondary lymphoid organs and tissues. Thus, the NS can directly affect the immune system by using a network of nerve fibers in the thymus, spleen, lymph nodes, and bone marrow (44, 45). Using nerve fibers, neurotransmitters penetrate remote places of the body, interacting with monocytes (macrophages), lymphocytes, and granulocytes, which contain receptors specific for them.
It was found that mice with autism spectrum disorders had significantly more dendritic cells than normally developing test subjects. A higher level of dendritic cells called plasmacytoid was linked to the occurrence of regression along with the subsequent occurrence of autistic behavior (45). Also, a link was established between this late appearance of the disease pattern and the increase in the cerebellar amygdala. Previous studies also found a link between the increase in this part of the brain and autism, in particular with increased social incompetence and anxiety.
Altered immune function in NL3R451C mice
The review of the existing literature shows that synaptic genes’ mutations promote GI dysfunction due to motility in ENS. Likewise, the CHD8 gene contributes to cell adhesion mutation, NL3R451C in mice is expressed in immune system function alterations (46). The negative changes in the gastrointestinal system are also inherent to the presentation of NL3R451C in mice (46, 47). It is important to emphasize that there is still insufficient information regarding the alterations of the immune system in ASD, which makes it evident that further research is needed.
Hypothesis
The present project will utilize immunocytochemical and histological strategies to evaluate histopathological changes in NL3R451C and Shank3 in mice. It is expected to reveal changes in immune responses and neuro-immune system interactions in the gut-brain axis. The results of this study are likely to be useful to a better understanding of the connection between GI and ENS, which will also affect the overall presentation of the given theme in terms of ASD and its potential treatment.
Aims
Based on the literature review presented above it becomes evident that there several needs that should be addressed in this project:
- To scrutinize Shank3 mouse colon tissue as well as histopathological changes in NL3R451C;
- To evaluate alterations in immune cell indicators using immunocytochemistry in NL3R451C and Shank3 mouse colon tissue analysis;
- To elaborate on an innovative strategy for assessing mucous thickness in the caecum.
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