Ube3a reinstatement mitigates epileptogenesis in Angelman syndrome model mice
Bin Gu, … , Serena M. Dudek, Benjamin D. Philpot
Bin Gu, … , Serena M. Dudek, Benjamin D. Philpot
Published January 2, 2019; First published October 23, 2018
Citation Information: J Clin Invest. 2019;129(1):163-168. https://doi.org/10.1172/JCI120816.
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Concise Communication Neuroscience

Ube3a reinstatement mitigates epileptogenesis in Angelman syndrome model mice

Abstract

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.

Authors

Bin Gu, Kelly E. Carstens, Matthew C. Judson, Katherine A. Dalton, Marie Rougié, Ellen P. Clark, Serena M. Dudek, Benjamin D. Philpot

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Figure 1

AS mice exhibit exaggerated epileptogenesis.

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AS mice exhibit exaggerated epileptogenesis. (A) Experimental paradigm o...
(A) Experimental paradigm of flurothyl kindling and retest followed by kainic acid–induced (repeated low-dose injection of 5 mg/kg i.p. every 30 minutes) or hyperthermia-induced seizure. Latency to (B) myoclonic and (C) generalized seizure in WT and AS model mice during flurothyl kindling and retest. ##P < 0.01 compared with day 8 of AS model mice; ****P < 0.0001 compared with WT; 2-way ANOVA with Bonferroni’s post hoc test. (D) Representative EEG trace of a spontaneous recurrent seizure (SRS) with corresponding spectrogram recorded from a WT mouse during the incubation period. (E) Group analysis of SRS incidence, recorded every other day during the 28-day incubation period following flurothyl kindling. (F) Correlation for individual WT (gray) and AS (green) mice between SRS frequency during incubation period and myoclonic seizure threshold at flurothyl retest. (G) Latency to the onset of repeated low-dose injection of kainic acid–induced EEG and class 4 to 5 behavioral seizure in kindled WT (n = 8) and AS (n = 9) model mice. *P < 0.05, **P < 0.01 by unpaired t test. (H) Hyperthermia-induced seizure incidence and body temperature at which generalized seizure occurred in kindled WT (n = 4) and AS (n = 7) model mice.