title: Neuropathological Mechanisms of Seizures in Autism Spectrum Disorder.
abstract: This manuscript reviews biological abnormalities shared by autism spectrum disorder (ASD) and epilepsy. Two neuropathological findings are shared by ASD and epilepsy: abnormalities in minicolumn architecture and γ-aminobutyric acid (GABA) neurotransmission. The peripheral neuropil, which is the region that contains the inhibition circuits of the minicolumns, has been found to be decreased in the post-mortem ASD brain. ASD and epilepsy are associated with inhibitory GABA neurotransmission abnormalities including reduced GABAA and GABAB subunit expression. These abnormalities can elevate the excitation-to-inhibition balance, resulting in hyperexcitablity of the cortex and, in turn, increase the risk of seizures. Medical abnormalities associated with both epilepsy and ASD are discussed. These include specific genetic syndromes, specific metabolic disorders including disorders of energy metabolism and GABA and glutamate neurotransmission, mineral and vitamin deficiencies, heavy metal exposures and immune dysfunction. Many of these medical abnormalities can result in an elevation of the excitatory-to-inhibitory balance. Fragile X is linked to dysfunction of the mGluR5 receptor and Fragile X, Angelman and Rett syndromes are linked to a reduction in GABAA receptor expression. Defects in energy metabolism can reduce GABA interneuron function. Both pyridoxine dependent seizures and succinic semialdehyde dehydrogenase deficiency cause GABA deficiencies while urea cycle defects and phenylketonuria cause abnormalities in glutamate neurotransmission. Mineral deficiencies can cause glutamate and GABA neurotransmission abnormalities and heavy metals can cause mitochondrial dysfunction which disrupts GABA metabolism. Thus, both ASD and epilepsy are associated with similar abnormalities that may alter the excitatory-to-inhibitory balance of the cortex. These parallels may explain the high prevalence of epilepsy in ASD and the elevated prevalence of ASD features in individuals with epilepsy.
authors.affiliation: Autism Research Program, Arkansas Children's Research InstituteLittle Rock, AR, USA; Department of Pediatrics, University of Arkansas for Medical SciencesLittle Rock, AR, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Frye
authors.affiliation: Department of Biomedical Sciences, University of South Carolina School of Medicine Greenville Greenville, SC, USA.
authors.forename: Manuel F
authors.initials: MF
authors.lastname: Casanova
authors.affiliation: Department of Psychiatry, University of Minnesota Medical School Minneapolis, MN, USA.
authors.forename: S Hossein
authors.initials: SH
authors.lastname: Fatemi
authors.affiliation: Department of Psychiatry, University of Minnesota Medical School Minneapolis, MN, USA.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Folsom
authors.affiliation: Department of Psychiatry, University of Minnesota Medical School Minneapolis, MN, USA.
authors.forename: Teri J
authors.initials: TJ
authors.lastname: Reutiman
authors.affiliation: Serenity Health Care Center Waukesha, WI, USA.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Brown
authors.affiliation: Autism Research Institute San Diego, CA, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Edelson
authors.affiliation: Autism Research Program, Arkansas Children's Research InstituteLittle Rock, AR, USA; Department of Pediatrics, University of Arkansas for Medical SciencesLittle Rock, AR, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Slattery
authors.affiliation: School for Engineering of Matter, Transport, and Energy, Arizona State University Tempe, AZ, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: Adams
keywords: autism spectrum disorder; epilepsy; excitatory-to-inhibitory cortical balance; gamma-aminobutyric acid; genetic syndrome; metabolic disorders; seizures