Represents a Lomitapide Mesylate strong point of shared biology between human ASD and the MIA model. One of the first structural brain abnormalities found in children with ASD was hypoplasia of the cerebellar vermis that preferentially affected lobules VI and VII. This has also been documented in adults with Fragile X Orbifloxacin Syndrome. Cerebellar Purkinje cells are large, fast-spiking, GABAergic, inhibitory neurons that are particularly sensitive to bioenergetic supply and demand problems, and to toxic exposures. Our finding of preserved cerebellar Purkinje cell numbers at 16 weeks of age in the MIA model with antipurinergic therapy supports the notion that the rate of postnatal Purkinje cell loss is dynamic and can be regulated by environmental factors. In the MIA mouse model, antipurinergic therapy slows the rate of Purkinje cell loss from 6 to 16 weeks of age. Like human autism spectrum disorders, the MIA mouse model of ASD has both core behavioral abnormalities, and multisystem comorbidities that emerge as a consequence of underlying metabolic disturbances. Our results support the paradigm that all of the observed metabolic disturbances in this model are a manifestation of the conserved cell danger response. The CDR therefore lies at or near the root cause of the neurodevelopmental and biochemical abnormalities that characterize the ASD-like features in this model. Extracellular ATP is a mitokine and well-known danger signal that we hypothesized initiates and sustains the cellular danger response in autism spectrum disorders. In related studies we found that direct systemic injection of nucleotides like ATP and ADP caused rapid hypothermia 
by decreasing mitochondrial oxygen consumption and tissue oxygen demand. Hypothermia from systemic nucleotide injection has been studied in the fields of torpor and hibernation physiology. We found that a convenient marker of the persistent cellular danger response in the poly model is relative hypothermia of about 0.5uC. Hypothermia was associated with an increase in the maximal enzymatic rates, but not the mass, of brain mitochondrial respiratory chain complexes I and IV. Treatment with suramin decreased brain mitochondrial activity to normal, increased the whole body oxygen consumption in the MIA animals, and increased the body temperature to normal. The combination of higher mitochondrial electron transport activities measured in vitro and decreased basal oxygen consumption measured in vivo implies a novel increase in mitochondrial coupling efficiency and increased reserve capacity in ASD that is similar to that seen with exercise training. We did not further investigate this phenomenon in this study. Purinergic P2Y2 receptors and their phosphorylated effectors, ERK1/2 and CAMKII, are downregulated by chronic nucleotide stimulation in a process that leads to desensitization. Our finding of downregulation of these purinergic receptors and their effectors is strong evidence for chronically elevated purinergic signaling in the poly model. Together, these findings are consistent with the notion that hyperpurinergia is a causal factor that initiates and maintains the cellular danger response in the MIA model of ASD. Suramin treatment corrected both the hyperpurinergia and the multisystem abnormalities in this model. We quantified the expression of the Fragile X protein in cerebral synaptosomes because deficiency is a cause of autism spectrum disorders.