Immune-Glutamatergic Dysfunction as a Central Mechanism of the Autism Spectrum Disorders

Abstract

Despite the great number of observations being made concerning cellular and the molecular dysfunctions associated with autism spectrum disorders (ASD), the basic central mechanism of these disorders has not been proposed in the major scientific literature. Our review brings evidence that most heterogeneous symptoms of ASD have a common set of events closely connected with dysregulation of glutamatergic neurotransmission in the brain with enhancement of excitatory receptor function by pro-inflammatory immune cytokines as the underlying mechanism. We suggest that environmental and dietary excitotoxins, mercury, fluoride, and aluminum can exacerbate the pathological and clinical problems by worsening excitotoxicity and by microglial priming. In addition, each has effects on cell signaling that can affect neurodevelopment and neuronal function. Our hypothesis opens the door to a number of new treatment modes, including the nutritional factors that naturally reduce excitotoxicity and brain inflammation.

Environmental factors associated with autism spectrum disorder: a scoping review for the years 2003–2013

“…According to the reviews based mainly on animal and human clinical studies, early-life immune insults such as toxic substances, food additives or stress may result in a cascade of excitotoxicity in the brain, [197][198][199] and may be related to dysregulation of glutamate neurotransmission. 199,200 This cascade may trigger production of proinflammatory cytokines, resulting in chronic inflammation affecting neurodevelopment.…”

Is Encephalopathy a Mechanism to Renew Sulfate in Autism?

“…It has been proposed that a key component of the neuronal dysfunction in ASD involves a dysregulation of glutamatergic neurotransmission in the brain [84]. A similar impairment has been identified for the hepatic encephalopathy associated with liver failure [85].…”

Theoretical aspects of autism: biomarkers—a review

“…Most heterogeneous symptoms of autism have a common set of events closely connected with dysregulation of glutamatergic neurotransmission in the brain with enhancement of excitatory receptor function by proinflammatory immune cytokines as the underlying mechanism (Blaylock and Strunecka, 2009). Environmental and dietary excitotoxins, mercury, fluoride, and aluminum, can exacerbate the pathological and clinical problems by worsening excitotoxicity and by microglial priming.…”

“…In addition, there is partial duplication of the metabotropic glutamate receptor 8 (GRM8) gene with a possible association with autism (Serajee et al, 2003). Glutamate is the principal excitatory neurotransmitter in the brain, acting at more than half of its synapses, and is directly involved in cognitive functions such as memory and learning (Jamain et al, 2002;Blaylock and Strunecka, 2009). Other genetic evidence, a high incidence of mutation of the GRM8 gene controlling the metabotropic GluR8 receptor subunit, which negatively modulates glutamate neurotransmission, was found in families having autistic children (Serajee et al, 2003).…”