期刊
NEURON
卷 90, 期 1, 页码 56-69出版社
CELL PRESS
DOI: 10.1016/j.neuron.2016.02.040
关键词
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资金
- NRSA [5F32NS077686, 1F31NS077847, T32-HD40127]
- Angelman Syndrome Foundation's Joseph E. Wagstaff fellowship
- Angelman Syndrome Foundation grants
- Simons Foundation SFARI Awards [274426, 275234]
- Netherlands Organization for Scientific Research grant-ZonNMW
- Hersenstichting grant
- NIMH [5RO1MHO93372]
- NINDS [5RO1NS039444, 1RO1NS085093]
- NINDS Center Grant [P30 NS045892]
- NICHD Center Grant [P30 HD03110]
- CSD Consortium [U01HG004080]
- KOMP Repository at UC Davis and CHORI [U42RR024244]
- NIH [U01HG004085]
Loss of maternal UBE3A causes Angelman syndrome (AS), a neurodevelopmental disorder associated with severe epilepsy. We previously implicated GABAergic deficits onto layer (L) 2/3 pyramidal neurons in the pathogenesis of neocortical hyperexcitability, and perhaps epilepsy, in AS model mice. Here we investigate consequences of selective Ube3a loss from either GABAergic or glutamatergic neurons, focusing on the development of hyperexcitability within L2/3 neocortex and in broader circuit and behavioral contexts. We find that GABAergic Ube3a loss causes AS-like increases in neocortical EEG delta power, enhances seizure susceptibility, and leads to presynaptic accumulation of clathrin-coated vesicles (CCVs)-all without decreasing GABAergic inhibition onto L2/3 pyramidal neurons. Conversely, glutamatergic Ube3a loss fails to yield EEG abnormalities, seizures, or associated CCV phenotypes, despite impairing tonic inhibition onto L2/3 pyramidal neurons. These results substantiate GABAergic Ube3a loss as the principal cause of circuit hyperexcitability in AS mice, lending insight into ictogenic mechanisms in AS.
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