| First Author | Teoh J | Year | 2020 |
| Journal | Neurobiol Dis | Volume | 134 |
| Pages | 104632 | PubMed ID | 31678406 |
| Mgi Jnum | J:296848 | Mgi Id | MGI:6472693 |
| Doi | 10.1016/j.nbd.2019.104632 | Citation | Teoh J, et al. (2020) Arfgef1 haploinsufficiency in mice alters neuronal endosome composition and decreases membrane surface postsynaptic GABAA receptors. Neurobiol Dis 134:104632 |
| abstractText | 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 (Arfgef1(fs)) in mice. Arfgef1(fs/+) pups exhibit signs of developmental delay, and Arfgef1(fs/+) adults have a significantly decreased threshold to induced seizures but do not experience spontaneous seizures. Histologically, the Arfgef1(fs/+) 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 Arfgef1(fs/+) neurons with an accompanying decrease in the number of GABAAR-containing recycling endosomes in cell body. Arfgef1(fs/+) neurons also display differences in the relative ratio of Arf6(+):Rab11(+):TrfR(+) recycling endosomes. Although the GABAAR-containing early endosomes in Arfgef1(fs/+) neurons are comparable to wildtype, Arfgef1(fs/+) 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. |
