Ube3a reinstatement mitigates epileptogenesis in Angelman syndrome model mice

J Clin Invest. 2019 Jan 2;129(1):163-168. doi: 10.1172/JCI120816. Epub 2018 Nov 19.


Angelman syndrome (AS) is a neurodevelopmental disorder in which epilepsy is common (~90%) and often refractory to antiepileptics. AS is caused by mutation of the maternal allele encoding the ubiquitin protein ligase E3A (UBE3A), but it is unclear how this genetic insult confers vulnerability to seizure development and progression (i.e., epileptogenesis). Here, we implemented the flurothyl kindling and retest paradigm in AS model mice to assess epileptogenesis and to gain mechanistic insights owed to loss of maternal Ube3a. AS model mice kindled similarly to wild-type mice, but they displayed a markedly increased sensitivity to flurothyl-, kainic acid-, and hyperthermia-induced seizures measured a month later during retest. Pathological characterization revealed enhanced deposition of perineuronal nets in the dentate gyrus of the hippocampus of AS mice in the absence of overt neuronal loss or mossy fiber sprouting. This pro-epileptogenic phenotype resulted from Ube3a deletion in GABAergic but not glutamatergic neurons, and it was rescued by pancellular reinstatement of Ube3a at postnatal day 21 (P21), but not during adulthood. Our results suggest that epileptogenic susceptibility in AS patients is a consequence of the dysfunctional development of GABAergic circuits, which may be amenable to therapies leveraging juvenile reinstatement of UBE3A.

Keywords: Epilepsy; Neurological disorders; Neuroscience.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angelman Syndrome* / genetics
  • Angelman Syndrome* / metabolism
  • Angelman Syndrome* / pathology
  • Angelman Syndrome* / therapy
  • Animals
  • Disease Models, Animal
  • Humans
  • Mice
  • Mossy Fibers, Hippocampal* / metabolism
  • Mossy Fibers, Hippocampal* / pathology
  • Seizures* / genetics
  • Seizures* / metabolism
  • Seizures* / pathology
  • Seizures* / therapy
  • Ubiquitin-Protein Ligases* / genetics
  • Ubiquitin-Protein Ligases* / metabolism


  • Ube3a protein, mouse
  • Ubiquitin-Protein Ligases