PT  - JOURNAL ARTICLE
AU  - JiaJie Teoh
AU  - Narayan Subramanian
AU  - Maria Elena Pero
AU  - Francesca Bartolini
AU  - Ariadna Amador
AU  - Ayla Kanber
AU  - Damian Williams
AU  - Sabrina Petri
AU  - Mu Yang
AU  - Andrew S. Allen
AU  - Jules Beal
AU  - Sheryl R. Haut
AU  - Wayne N. Frankel
TI  - <em>Arfgef1</em> haploinsufficiency in mice alters neuronal endosome composition and decreases membrane surface postsynaptic GABA<sub>A</sub> receptors
AID  - 10.1101/743625
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 743625
4099  - http://biorxiv.org/content/early/2019/09/08/743625.short
4100  - http://biorxiv.org/content/early/2019/09/08/743625.full
AB  - 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 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 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.HighlightsArfgef1fs/+ mice have lower seizure threshold but no spontaneous seizure.Arfgef1fs/+ neurons show reduced dendritic surface GABAAR.Arfgef1fs/+ neurons have decreased GABAAR-containing recycling endosome accompanied with an increase in GABAAR-containing lysosomes.