Rescue of the Functional Alterations of Motor Cortical Circuits in Arginase Deficiency by Neonatal Gene Therapy.

摘要: 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 arginase expression affects the excitability synaptic connectivity cortical neurons in developing brain, we used anatomical, ultrastructural, electrophysiological techniques to determine single-copy double-copy deletion circuits mice. We find that results decreased dendritic complexity, excitatory inhibitory synapse numbers, intrinsic excitability, altered transmission layer 5 motor neurons. Hepatic gene therapy using adeno-associated virus rescued nearly all these abnormalities when administered neonatal homozygous knock-out animals. Therefore, therapeutic strategies can reverse physiological anatomical markers therefore may be benefit for neurological disabilities this syndrome. SIGNIFICANCE STATEMENT These studies are one few investigations try understand underlying dysfunction occurs disorders only examine deficiency. have demonstrated by multiple modalities that, murine neurons, gradation exists based functional copy number arginase: altered, there density asymmetrical perisomatic synapses, analysis complexity lowest knock-out. With administration expressing arginase, near-total recovery circuits, supporting concept prevent occur