Arfgef1 haploinsufficiency in mice alters neuronal endosome composition and decreases membrane surface postsynaptic GABAA receptors

Jia Jie Teoh, Narayan Subramanian, Maria Elena Pero, Francesca Bartolini, Ariadna Amador, Ayla Kanber, Damian Williams, Sabrina Petri, Mu Yang, Andrew S. Allen, Jules C. Beal, Sheryl R. Haut, Wayne N. Frankel

Research output: Contribution to journalArticle

Abstract

ARFGEF1 encodes a guanine exchange factor involved in intracellular vesicle trafficking, and is a candidate gene for childhood genetic epilepsies. To model ARFGEF1 haploinsufficiency observed in a recent Lennox Gastaut Syndrome patient, we studied a frameshift mutation (Arfgef1fs) in mice. Arfgef1fs/+ pups exhibit signs of developmental delay, and Arfgef1fs/+ adults have a significantly decreased threshold to induced seizures but do not experience spontaneous seizures. Histologically, the Arfgef1fs/+ brain exhibits a disruption in the apical lining of the dentate gyrus and altered spine morphology of deep layer neurons. In primary hippocampal neuron culture, dendritic surface and synaptic but not total GABAA receptors (GABAAR) are reduced in Arfgef1fs/+ neurons with an accompanying decrease in the number of GABAAR-containing recycling endosomes in cell body. Arfgef1fs/+ neurons also display differences in the relative ratio of Arf6+:Rab11+:TrfR+ recycling endosomes. Although the GABAAR-containing early endosomes in Arfgef1fs/+ neurons are comparable to wildtype, Arfgef1fs/+ neurons show an increase in the number of GABAAR-containing lysosomes in dendrite and cell body. Together, the altered endosome composition and decreased neuronal surface GABAAR results suggests a mechanism whereby impaired neuronal inhibition leads to seizure susceptibility.

Original languageEnglish (US)
Article number104632
JournalNeurobiology of Disease
Volume134
DOIs
StatePublished - Feb 2020

Keywords

  • Endocytic cycle
  • Epilepsy
  • GABA receptor
  • Lennox-Gastaut syndrome

ASJC Scopus subject areas

  • Neurology

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    Teoh, J. J., Subramanian, N., Pero, M. E., Bartolini, F., Amador, A., Kanber, A., Williams, D., Petri, S., Yang, M., Allen, A. S., Beal, J. C., Haut, S. R., & Frankel, W. N. (2020). Arfgef1 haploinsufficiency in mice alters neuronal endosome composition and decreases membrane surface postsynaptic GABAA receptors. Neurobiology of Disease, 134, [104632]. https://doi.org/10.1016/j.nbd.2019.104632