Written by Brett Weiss
Leo Kanner first defined the contemporary understanding of autism in 1943 as the inability to form normal and biologically determined emotional connections with others (Chaste & Leboyer, 2012). Prior to that, a Swiss psychiatrist named Paul Eugen Bleuler used the term in 1912 to define symptoms of schizophrenia. Hans Asperger used Bleuler’s term “autistic” to describe forms of childhood psychology in 1938. Asperger performed a study on four boys who did not understand the meaning of the words ‘polite’ or ‘respect’ and who had no respect for the authority of an adult. These boys also showed repetitive, stereotypic movements and habits all of which Asperger named “autistic psychopathy,” now called Asperger’s Syndrome. Hence, most experts consider Leo Kanner and Hans Asperger the ones who provided the basis of the modern study of autism (Park et al., 2016).
Modern-day clinicians define autism spectrum disorder (ASD) as a set of neurodevelopmental disorders that include lack of social interaction, along with lack of verbal and nonverbal communication in the first three years of life. The social behaviors that distinguish patients with ASD from neurotypicals include avoidance of eye contact, problems controlling emotions and understanding emotions of others, and a highly restricted range of activities and interests. Large-scale studies have revealed that the current prevalence of ASD is about 1%-2% (Kim et al., 2011). The prevalence of ASD has increased in the last few decades, partially due to DSM diagnostic criteria changes and younger age of diagnosis. At the same time, an increase in risk factors may contribute to increased prevalence. Males are two to three times more likely to receive an ASD diagnosis than females, which may result from under-recognition of females with ASD or female-specific protective effects against ASD (Park et al., 2016).
ASD is not a single disorder but rather constitutes a multifactorial disorder arising from genetic and non-genetic risk factors along with their interaction. A recurrence risk of significant developmental disorder is seen in 2% to 8% of siblings of children with ASD. The recurrence risk rises to 12% to 20% if one accounts for siblings showing impairment in a single behavioral domain associated with ASD. Most ASD experts agree that many genes contribute to the occurrence of ASD (the polygenic model).
Genetics studies in ASD have shown that a multitude of genetic alterations affecting a few biological pathways of brain development and plasticity contribute to ASD pathology. For example, the chromosomal abnormality 15q11-q13 duplication associates with ASD and affects synaptic plasticity. Also, some of the first genes associated with ASD affect synaptic function, namely NLGN3 and NLGN4X (also referred to as SHANK3). Whole-genome screening methods have revealed genetic structural abnormalities affecting genes involved in synaptic function. Studies of copy number variations (CNVs) have provided further evidence of these genetic structural abnormalities in genes involved in synaptic function. Many CNV studies have shown abnormalities in the NLGN-NRXN-SHANK pathway, along with other synaptic genes that include SynGAP and DLGAP2 (Chaste & Leboyer, 2012).
Many authors have also noted immune dysfunction in patients with ASD. Several studies have implicated aberrations in the peripheral immune system. These aberrations include T-cell dysfunction, autoantibody production, increased numbers of activated B cells and NK cells, and increased numbers of proinflammatory cytokines. Other studies have given evidence of microglial and astroglial activation in brains of patients with ASD. Prominent microglial activation was shown in cerebellum and cerebral white matter. This microglial activation may result from a primary insult to microglial function or unknown factors which disturb prenatal and/or postnatal central nervous system development (Chaste & Leboyer, 2012).
Differences in brain structures also exist when comparing neurotypicals with ASD patients. Patients with ASD have markedly affected frontal and temporal (side) regions of the brain. Researchers have recently implicated a structure in the temporal lobe, the amygdala, in ASD pathology from numerous neuropathological and neuroimaging studies. The amygdala lays toward the front end of the temporal lobe toward the medial (middle) portion of this brain structure. Neuroscientists have associated the amygdala with social abnormalities and aggressive behaviors in patients with ASD. The main functions of the amygdala include eye gaze and face processing. Patients with lesions to the amygdala have symptoms similar to patients with ASD in that they have fear processing abnormalities, poor modulation of memory with emotional content, and show an abnormal gaze when looking at a human face. Cellular abnormalities in the amygdala of patients with ASD include small neuron size and increased cell density compared with neurotypicals. Studies done which measured N-acetyl aspartate (NAA) in the amygdala region and the left cerebellar hemisphere of ASD subjects showed decreased levels of NAA in neurons of ASD subjects. This finding implies that decreased levels of NAA may be associated with immature neurons or hypofunctional neurons in ASD subjects (Park et al., 2016).
Another brain region associated with ASD pathology, the frontal cortex, plays important roles in higher-level control and executive function. People with frontal lobe deficits show high-order cognition deficits as well as language, social, and emotional dysfunction. All of these issues constitute symptoms of ASD. Some authors have reported excessive brain growth in infants with ASD, which is mostly attributable to frontal cortex growth (Park et al., 2016). Hence, some unknown pathology in patients with ASD may contribute to abnormal growth of the frontal cortex in neurodevelopment.
Authors have also associated neurotransmitter dysfunction with ASD. Studies of neurotransmitter dysfunction in ASD have involved serotonin, dopamine, GABA, glutamate, acetylcholine, and histamine. Of all neurotransmitters investigated in ASD pathology, serotonin ranks as the most studied. Serotonin facilitates production of new neurons (neurogenesis), cell migration, cell survival, synaptogenesis, and synaptic plasticity. Of note, high levels of serotonin in blood has been measured in ~45% of patients with ASD, pointing to the importance of serotonin in ASD pathology. In animal models studying high serotonin levels (hyperserotonemia), the high serotonin levels decreased motivation for socialization through inhibition of separation distress. This observation could account for the social impairments found in patients with ASD. Dopamine plays a key role in brain function, and the dysfunction of the dopaminergic system in patients with ASD has been widely recognized. Interestingly, antipsychotics used to treat ASD, risperidone and aripiprazole, act as antagonists to D1 dopamine receptors and partial agonists of D2 dopamine receptors. In mouse models, molecules that activate D1 dopamine receptors (agonists) produced typical autistic-like behaviors in normal mice, which exhibited significant deficits in sociability along with repetitive behaviors related to ASD. Molecules that inhibit D1 dopamine receptors (antagonists) blocked the behavioral changes associated with ASD. These results point to the importance of the dopaminergic system in ASD. Patients with ASD display perturbations in development of socialization, attention and perception skills, and motor activity, which all relate to the dopaminergic system. The balance between the excitatory glutamate neurotransmitter and the inhibitory GABA neurotransmitter may show disruption in ASD patients. Altered expression of genes in ASD patients related to these neurotransmitters have been observed. Such alterations may be linked to imbalances in the GABA and glutamate systems which may cause cognitive deficits and/or hyperactivity. ASD patients show remarkable abnormalities in the cholinergic system as well. Acetylcholine is associated with cognitive flexibility, attention, and the presence of stereotypical behaviors in patients with ASD. In patients with ASD, there is an irregular number of neurons in a forebrain cholinergic nucleus; these neurons also have an irregular structure. There is also a decreased level of choline, the precursor to acetylcholine, in the brains of patients diagnosed with ASD. The histamine neurotransmitter has been found to play a prominent role in cognition and sleep. The histaminergic system has been proposed as a target for future pharmacological intervention in patients with ASD as the histaminergic system has been found to play a key role in the homeostasis of most of the neurotransmitters (Eissa et al., 2018).
ASD constitutes a complex and polygenic disorder that involves a gene-environment interaction. While researchers have discovered attributes of ASD relating to brain structures, genetics, and neuropharmacology, much more research will need to occur for treatment of this disease. Some say that future research may entail searching for biomarkers in ASD, which are objectively measured and evaluated indicators of normal or pathogenic processes. Identification of biomarkers in ASD may help to begin treatment at earlier stages of ASD (Beversdorf, 2016).
Beversdorf DQ (2016). “Phenotyping, Etiological Factors, and Biomarkers: Toward Precision Medicine in Autism Spectrum Disorders.” J Dev Behav Pediatr 37(8): 659-73.
Chaste P and Leboyer M (2012). “Autism risk factors: genes, environment, and gene-environment interactions.” Dialogues Clin Neurosci 14(3): 281-92.
Eissa N, Al-Houqani M, Sadeq A, Ojha S, Sasse A, and Sadek B (2018). “Current Enlightenment About Etiology and Pharmacological Treatment of Autism Spectrum Disorder.” Front Neurosci 12(304): 1-20.
Kim YS, Leventhal BL, Koh YJ, fombonne E, Laska E, Lim EC, Cheon KA, Kim SJ, Kim YK, Lee H, Song DH, Grinker RR (2011). “Prevalence of autism spectrum disorders in a total population sample.” Am J Psychiatry 168: 904-912.
Park HR, Lee JM, Moon HE, Lee DS, Kim BN, Kim J, Kim DG, and Paek SH (2016). “A Short Review on the Current Understanding of Autism Spectrum Disorders.” Exp Neurobiol 25(1): 1-13.