Chronic cell danger response signaling tied to autism in mice
Autism spectrum disorders (ASDs) are complex neurodevelopmental disorders characterized by abnormalities in the development of language and social behavior and by repetitive behaviors. Both genetic and environmental factors can contribute to these abnormalities. More than a dozen physiological irregularities are associated with ASDs, making them very difficult to treat. The chances of finding a drug that addresses all of them are slim. Yet a research team led by Robert Naviaux, M.D., from the San Diego School of Medicine, San Diego, Calif., found that the drug suramin, a purinergic signaling inhibitor, corrects all the autism-associated abnormalities in an ASD mouse model (Naviaux et al. 2013; Autismspeaks.org 2013). Their results offer new opportunities for understanding and treating autism-related disorders.
A sustained cell danger response signal
The nucleotides ATP, ADP, UDP and UTP are usually thought of as the energy currency of the cell. However, they are also mitokines – molecules produced by the mitochondria that have intracellular, metabolic roles but, when released into the extracellular environment, act like molecular signals or cytokines. Among their many functions, mitokines bind to and regulate at least 15 different isoforms of purinergic receptors. These receptors occur on the surfaces of all cells and control a broad range of physiological mechanisms, including all those known to be autism-relevant. In its role as a mitokine, ATP is a damage-associated molecular pattern (DAMP). In the presence of pathogens and/or other stressors, it initiates the cell danger response (CDR) via purinergic receptors, activating innate immunity and inducing inflammation. Naviaux and his team suspected that some kind of stress – a genetic anomaly and/or an environmental insult (for examples, a pathogen, chemical, or radiation exposure) – during the brain's development triggers persistent ATP/purinergic signaling, sustains the CDR and causes the multi-system symptoms of ASDs.
The MIA model of autism
To model autism, the Naviaux team used the maternal immune activation (MIA) ASD model, a model that has been used extensively to study ASD- and schizophrenia-associated phenotypes. In this model, adult female C57BL/6J (000664) mice are injected with a synthetic, double-stranded RNA – poly(Inosine:Cytosine), abbreviated poly(IC) – at two vulnerable times, E12.5 and E17.5, during pregnancy. The injected poly(IC) simulates a viral infection and induces anorexia and a fever, which, during human pregnancy, is known to be an ASD risk factor. The pregnant females recover in about 24 hours. The exposure to poly(IC), however, is stored as a metabolic memory in the brain, gut and autonomic nervous system of the offspring. When they are exposed to poly(IC) again, they develop ASD- and schizophrenia-like abnormalities. The Naviaux team hypothesized that these abnormalities develop because the CDR is sustained by poly(IC)-induced hyperpurinergia and that the drug suramin, a well-studied inhibitor of purinergic signaling, would correct them.
Suramin corrects autism-associated abnormalities in the MIA mouse
Naviaux and his colleagues wanted to assess suramin's effects on already established ASD-like phenotypes. Therefore, they didn't begin treating the MIA mice with suramin until they were six weeks old. They found that suramin corrects all of the core ASD-associated abnormalities of the MIA mouse model.
- It normalizes social preference behavior, sensorimotor coordination and body temperature.
- It increases mitochondrial respiration and corrects mitochondrial respiratory chain hyperactivity without affecting body mass index, activity, weight and food or water consumption.
- It decreases unidentified electron-dense matrix material and restores post-synaptic density architecture.
- It normalizes the expression of two purinergic receptors and the phosphorylation of ERK1, ERK2, and CAMKII, which all modulate purinergic signaling.
- It normalizes the expression of the fragile X mental retardation protein (FMRP), which inhibits the translation of many inflammatory cytokines.
- It increases the synaptosomal expression of the nicotinic acetylcholine receptor subunit 7 (nAchR7), an anti-inflammatory regulator of innate immunity, indicating that it may be a therapeutic target for ASDs.
- It prevents cerebellar Purkinje cell loss.
The Naviaux team was particularly struck by suramin's ability to prevent the loss of cerebellar Purkinje cells, inhibitory neurons that are especially sensitive to toxins and perturbations in the cell's energy balance. The loss of these cells is a common feature of ASDs and fragile X-associated tremor ataxia syndrome (FXTAS).
In summary, the Naviaux team's results support the hypothesis that the ASD-like abnormalities in the MIA mouse model are due to a sustained cell danger response (CDR) caused by poly(IC)-induced hyperpurinergic signaling. Excess extracellular ATP is suspected of playing a major role in sustaining the CDR. Naviaux and his colleagues were the first to report that a single purinergic inhibitor can correct or improve both the core behavioral symptoms and numerous multi-system abnormalities of the MIA model. The inhibitor they used, suramin, did not induce any adverse side effects. These findings indicate that a better understanding of the CDR and ATP/purinergic signaling could significantly improve ASD therapies.