Cellular and Molecular Biology of Autism Spectrum Disorders

Autism spectrum disorders (ASD) are a group of related neurodevelopmental disorders, which includes autism (autistic disorder), Asperger syndrome, Rett syndrome, pervasive developmental disorder-not-otherwise specified (PDD-NOS), and childhood disintegrative disorder (CDD). This chapter provides the review of recent knowledge about clinical symptoms and criteria for diagnosis of heterogeneous symptoms of ASD. An alarming increase in the prevalence of ASD is of great concern to practicing pediatricians and psychiatrists. Some people attribute the increases over time in the frequency of ASD to factors such as new administrative classifications, changing diagnostic criteria, and heightened awareness. It is evident, that no single factor or a simple explanation can account for the increase. ASD are highly genetic and multifactorial, with many risk factors acting together. There is no therapy of the core symptoms of ASD at present. Several studies suggest that 50-75% of children with ASD are using complementary alternative medicine. Families and clinicians need access to theoretical and clinical evidence to assist them in the choice of therapies.</p>

<p>The cerebellum is the most commonly affected part of the brain in autistic spectrum disorders (ASDs). The histopathological changes strongly indicate selected damage to particular cell groups and lobules of the cerebellum rather than diffuse injury. A number of studies have shown injury and abnormal development of the vermis of the cerebellum, with a predominance of neuronal loss among Purkinje cells and granule cells. In addition, one see abnormal pathway development indicating intrauterine damage or damage occurring during the early postnatal period. Several studies have shown abnormalities of glutamate receptors (GluRs) of various kinds, including metabotropic GluRs (mGluRs). In this chapter, I review the histopathologic findings within the ASD cerebellum and demonstrate evidence for immunoexcitotoxicity affecting cerebellar neurodevelopment as well as evidence for early neurodegeneration. Newer studies have shown that the cerebellum may have significant cognitive and higher cortical functions, either by way of its connections to prefrontal-limbic areas or more indirect pathways.</p>

<p>Despite the great number of observations being made concerning cellular and molecular dysfunctions associated with autism spectrum disorders (ASD), an integrative and unifying mechanism to explain the heterogeneous symptoms and etiology of ASD has not been proposed in the major scientific literature. We offer the explanation of potential etiology of ASD as dysregulation of glutamatergic neurotransmission with underlying interactions between chronic microglial activation and the excitotoxic cascade playing the central role. This chapter summarizes current knowledge of the structural and functional diversity of glutamate receptors (GluRs) and excitatory amino acid transporters. Recent research of the autism genome also supports the view that abnormalities in genes connected with glutamate neurotransmission and disturbed regulation of glutamate pathways may be directly involved in ASD. We further suggest that the increasing prevalence of ASD during the last decades might reflect the synergistic action of an increased burden of new excitotoxic factors. In this chapter we discuss the effects of dietary excitatory amino acids, mainly glutamate and aspartate, which could exacerbate the pathological and clinical symptoms of ASD. The mechanism of excitotoxicity is the topic of the next chapter.</p>

<p>Autism has undergone a tremendous amount of study, and a number of often seemingly unconnected disorders have been disclosed. Yet, despite an enormous amount of study, no central mechanism to explain the causation of this syndrome or why it affects only a subset of children has come forth. In this chapter I propose such a central mechanism that explains a great number of biochemical, histological, neurodevelopmental and systemic dysfunctions, as well as behavioral findings in autism spectrum disorders (ASD). Since the discovery of excitotoxicity by Olney in 1968, neuroscientists have determined that not only is glutamate a neurotransmitter, but it is the most abundant neurotransmitter in the brain, exceeding the more traditional neurotransmitters combined. Recent studies have also shown that glutamatergic receptors (GluRs) interact with other receptors, not only neurotransmitters, but also immune receptors, in a way that can alter their sensitivity. Chronic brain inflammation is known to dramatically enhance the sensitivity of N-methyl-D-aspartic acid (NMDA) and α- amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) type GluRs and interfere with glutamate removal from the extraneuronal space, where it can trigger excitotoxicity and abnormal synaptic and dendritic physiology over a prolonged period. Importantly, neuroscience studies have clearly shown that sequential systemic immune stimulation can not only activate the brain ’ s immune system, microglia and astrocytes, but that there occurs an amplified response to both subsequent stimulation, either systemic or within the CNS. The ASD child is exposed to such sequential immune stimulation via a growing number of vaccines, recurrent infections, chemical toxins and persistent viral infections.</p>

<p>A great number of studies have been done examining immune function in children with autism spectrum disorders (ASD). Most of these studies have demonstrated immune dysfunction, especially involving cellular immunity. Important to the immunoexcitotoxicity hypothesis is the finding that macrophages and lymphocytes from ASD children have been shown to demonstrate an amplified release of pro-inflammatory cytokines with stimulation, especially in those having gastrointestinal (GI) symptoms. Because of the intimate connection between the gut and brain, hyperimmune responses from the gut, vial vagal afferents, can rapidly activate brain microglia, leading to an exaggerated innate immune response within the brain. It has also been shown that ASD children often react to food peptides, such as gliadin, gluten and casein as well as a number of bacterial and fungal antigens, all of which can exaggerate immunoexcitotoxicity. The finding of cross-reacting food antigen with brain components also indicates the presence of bystander damage and would trigger immunoexcitotoxicity as well.</p>

<p>Growing evidence confirms that up to 95% of autistic children suffer with the dysfunctions of the gastrointestinal (GI) system. We discuss the cellular and molecular mechanisms underlying these disturbances. Some researchers, physicians, and health care professionals suggest that beneficial effects of dietary intervention on behavior and cognition of some autistic children indicate a functional relationship between the GI tract (GIT) and the CNS pathology of ASD. A possible genetic cause for the association of autism and GI disease is discussed. GI disorders are not included in diagnostic criteria for ASD. Clinical and practical experiences provide the support for association between inflammatory bowel disease and ASD.</p>

<p>Metabolic dysfunctions have not been extensively studied in ASD despite the fact that chronic biochemical imbalance is often a primary factor in the development of several neurological diseases. Substantial percentages of autistic patients display peripheral markers of mitochondrial energy metabolism dysfunction, such as elevated lactate and alanine levels in blood and serum carnitine deficiency. We assess the reported biochemical changes in the blood and evidence based on the exploration of brain imaging studies. Even though alterations in mitochondrial and cellular energy metabolism are not specific for ASD, they indicate the potential ethiopathological events. Evidence from several laboratories similarly indicates that biomarkers of oxidative stress may be increased in some autistic children. One of the best documented biochemical changes in ASD is a decrease in cellular glutathione (GSH) levels, a major intracellular antioxidant, and an increase in oxidized glutathione (GSSG). Alterations in methionine -homocysteine cycle have been studied in details in ASD. Significant changes in transmethylation and transsulfuration metabolites in plasma from autistic children were reported. The new finding indicates a significant decrease in methylation capacity and redox potential. Metabolic and mitochondrial defects may have toxic effects on brain cells, causing neuronal loss and altered modulation of neurotransmission systems. The observations of biochemical changes thus further support that the antioxidant therapy and supplementation with some vitamins could prevent and restore the energy metabolism of individuals with ASD. This chapter brings evidence of the impact of observed biochemical changes in ASD for potential amelioration of ASD symptoms and for evidence-based therapy.</p>