title: Antipurinergic therapy corrects the autism-like features in the poly(IC) mouse model.
abstract: BACKGROUND
  Autism spectrum disorders (ASDs) are caused by both genetic and environmental factors. Mitochondria act to connect genes and environment by regulating gene-encoded metabolic networks according to changes in the chemistry of the cell and its environment. Mitochondrial ATP and other metabolites are mitokines-signaling molecules made in mitochondria-that undergo regulated release from cells to communicate cellular health and danger to neighboring cells via purinergic signaling. The role of purinergic signaling has not yet been explored in autism spectrum disorders.
  
  
  OBJECTIVE
  We used the maternal immune activation (MIA) mouse model of gestational poly(IC) exposure and treatment with the non-selective purinergic antagonist suramin to test the role of purinergic signaling in C57BL/6J mice.
  
  
  RESULTS
  We found that antipurinergic therapy (APT) corrected 16 multisystem abnormalities that defined the ASD-like phenotype in this model. These included correction of the core social deficits and sensorimotor coordination abnormalities, prevention of cerebellar Purkinje cell loss, correction of the ultrastructural synaptic dysmorphology, and correction of the hypothermia, metabolic, mitochondrial, P2Y2 and P2X7 purinergic receptor expression, and ERK1/2 and CAMKII signal transduction abnormalities.
  
  
  CONCLUSIONS
  Hyperpurinergia is a fundamental and treatable feature of the multisystem abnormalities in the poly(IC) mouse model of autism spectrum disorders. Antipurinergic therapy provides a new tool for refining current concepts of pathogenesis in autism and related spectrum disorders, and represents a fresh path forward for new drug development.
authors.affiliation: The Mitochondrial and Metabolic Disease Center, University of California San Diego School of Medicine, San Diego, California, USA. Naviaux@ucsd.edu
authors.forename: Robert K
authors.initials: RK
authors.lastname: Naviaux
authors.forename: Zarazuela
authors.initials: Z
authors.lastname: Zolkipli
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nakayama
authors.forename: Jane C
authors.initials: JC
authors.lastname: Naviaux
authors.forename: Thuy P
authors.initials: TP
authors.lastname: Le
authors.forename: Michael A
authors.initials: MA
authors.lastname: Schuchbauer
authors.forename: Mihael
authors.initials: M
authors.lastname: Rogac
authors.forename: Qingbo
authors.initials: Q
authors.lastname: Tang
authors.forename: Laura L
authors.initials: LL
authors.lastname: Dugan
authors.forename: Susan B
authors.initials: SB
authors.lastname: Powell
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D004195:Disease Models, Animal; D004579:Electron Transport; D004734:Energy Metabolism; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000378:metabolism; D007035:Hypothermia / Q000188:drug therapy / Q000378:metabolism; D007136:Immunoglobulins / Q000097:blood / Q000276:immunology; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D011070:Poly I-C / Q000009:adverse effects; D011597:Psychomotor Performance; D011689:Purkinje Cells / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D015398:Signal Transduction; D012919:Social Behavior; D013498:Suramin / Q000008:administration & dosage*; D013574:Synaptosomes / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D003345:Corticosterone; D051860:Fragile X Messenger Ribonucleoprotein 1; D007136:Immunoglobulins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D011070:Poly I-C; D011978:Receptors, Nicotinic; D013498:Suramin