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

Publication ,  Journal Article
Teoh, J; Subramanian, N; Pero, ME; Bartolini, F; Amador, A; Kanber, A; Williams, D; Petri, S; Yang, M; Allen, AS; Beal, J; Haut, SR; Frankel, WN
September 8, 2019

encodes a guanine exchange factor involved in intracellular vesicle trafficking, and is a candidate gene for childhood genetic epilepsies. To model haploinsufficiency observed in a recent Lennox Gastaut Syndrome patient, we studied a frameshift mutation ) in mice. pups exhibit signs of developmental delay, and adults have a significantly decreased threshold to induced seizures but do not experience spontaneous seizures. Histologically, the 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 GABA receptors (GABAR) are reduced in neurons with an accompanying decrease in GABAR-containing recycling endosomes in cell body. neurons also display differences in the relative ratio of Arf6:Rab11:TrfR recycling endosomes. Although the GABAR-containing early endosomes in neurons are comparable to wildtype, neurons show an increase in GABAR-containing lysosomes in dendrite and cell body. Together, the altered endosome composition and decreased neuronal surface GABAR results suggests a mechanism whereby impaired neuronal inhibition leads to seizure susceptibility.

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September 8, 2019
 

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Teoh, J., Subramanian, N., Pero, M. E., Bartolini, F., Amador, A., Kanber, A., … Frankel, W. N. (2019). Arfgef1 haploinsufficiency in mice alters neuronal endosome composition and decreases membrane surface postsynaptic GABAA receptors. https://doi.org/10.1101/743625
Teoh, JiaJie, Narayan Subramanian, Maria Elena Pero, Francesca Bartolini, Ariadna Amador, Ayla Kanber, Damian Williams, et al. “Arfgef1 haploinsufficiency in mice alters neuronal endosome composition and decreases membrane surface postsynaptic GABAA receptors,” September 8, 2019. https://doi.org/10.1101/743625.
Teoh J, Subramanian N, Pero ME, Bartolini F, Amador A, Kanber A, Williams D, Petri S, Yang M, Allen AS, Beal J, Haut SR, Frankel WN. Arfgef1 haploinsufficiency in mice alters neuronal endosome composition and decreases membrane surface postsynaptic GABAA receptors. 2019 Sep 8;

DOI

Publication Date

September 8, 2019