title: Rescue of the Functional Alterations of Motor Cortical Circuits in Arginase Deficiency by Neonatal Gene Therapy.
abstract: Arginase 1 deficiency is a urea cycle disorder associated with hyperargininemia, spastic diplegia, loss of ambulation, intellectual disability, and seizures. To gain insight on how loss of arginase expression affects the excitability and synaptic connectivity of the cortical neurons in the developing brain, we used anatomical, ultrastructural, and electrophysiological techniques to determine how single-copy and double-copy arginase deletion affects cortical circuits in mice. We find that the loss of arginase 1 expression results in decreased dendritic complexity, decreased excitatory and inhibitory synapse numbers, decreased intrinsic excitability, and altered synaptic transmission in layer 5 motor cortical neurons. Hepatic arginase 1 gene therapy using adeno-associated virus rescued nearly all these abnormalities when administered to neonatal homozygous knock-out animals. Therefore, gene therapeutic strategies can reverse physiological and anatomical markers of arginase 1 deficiency and therefore may be of therapeutic benefit for the neurological disabilities in this syndrome.
  
  
  
  These studies are one of the few investigations to try to understand the underlying neurological dysfunction that occurs in urea cycle disorders and the only to examine arginase deficiency. We have demonstrated by multiple modalities that, in murine layer 5 cortical neurons, a gradation of abnormalities exists based on the functional copy number of arginase: intrinsic excitability is altered, there is decreased density in asymmetrical and perisomatic synapses, and analysis of the dendritic complexity is lowest in the homozygous knock-out. With neonatal administration of adeno-associated virus expressing arginase, there is near-total recovery of the abnormalities in neurons and cortical circuits, supporting the concept that neonatal gene therapy may prevent the functional abnormalities that occur in arginase deficiency.
authors.affiliation: Departments of Surgery.
authors.forename: Gloria
authors.initials: G
authors.lastname: Cantero
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California Davis, School of Medicine, Sacramento, California 95817.
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: Liu
authors.affiliation: Neurostructural Research Labs, Tampa, Florida 33637.
authors.forename: Ronald F
authors.initials: RF
authors.lastname: Mervis
authors.affiliation: Neurology.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Lazaro
authors.affiliation: Pediatrics, Human Genetics, Intellectual and Developmental Disabilities Research Center, University of California Los Angeles, Los Angeles, California 90095, Semel Institute for Neuroscience, Los Angeles, California 90095, and.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Cederbaum
authors.affiliation: Neurology, Intellectual and Developmental Disabilities Research Center, University of California Los Angeles, Los Angeles, California 90095, Semel Institute for Neuroscience, Los Angeles, California 90095, and West Los Angeles Veterans Affairs Medical Center, Los Angeles, California 90073.
authors.forename: Peyman
authors.initials: P
authors.lastname: Golshani
authors.affiliation: Departments of Surgery, Psychiatry, Medicine, and Molecular and Medical Pharmacology, David Geffen School of Medicine, and Intellectual and Developmental Disabilities Research Center, University of California Los Angeles, Los Angeles, California 90095, Semel Institute for Neuroscience, Los Angeles, California 90095, and glipshutz@mednet.ucla.edu.
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Lipshutz
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000641:Ammonia / Q000097:blood; D000818:Animals; D000831:Animals, Newborn; D001119:Arginase / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D004195:Disease Models, Animal; D015316:Genetic Therapy; D020162:Hyperargininemia / Q000097:blood / Q000473:pathology* / Q000628:therapy*; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D009044:Motor Cortex / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D009415:Nerve Net / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure; D010852:Picrotoxin / Q000494:pharmacology; D020127:Recovery of Function / Q000502:physiology*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013569:Synapses / Q000648:ultrastructure; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D000641:Ammonia; D001119:Arginase; D010852:Picrotoxin; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; C544448:Arg1 protein, mouse
keywords: adeno-associated virus; arginase deficiency; electrophysiology; gene therapy; motor cortex; synapses