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 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

Fingerprint

Haploinsufficiency
Endosomes
GABA-A Receptors
Neurons
Membranes
Seizures
Frameshift Mutation
Dentate Gyrus
Guanine
Dendrites
Lysosomes
Epilepsy
Spine
Brain
Genes

Keywords

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

ASJC Scopus subject areas

  • Neurology

Cite this

Arfgef1 haploinsufficiency in mice alters neuronal endosome composition and decreases membrane surface postsynaptic GABAA receptors. / Teoh, Jia Jie; Subramanian, Narayan; Pero, Maria Elena; Bartolini, Francesca; Amador, Ariadna; Kanber, Ayla; Williams, Damian; Petri, Sabrina; Yang, Mu; Allen, Andrew S.; Beal, Jules; Haut, Sheryl R.; Frankel, Wayne N.

In: Neurobiology of Disease, Vol. 134, 104632, 02.2020.

Research output: Contribution to journalArticle

Teoh, JJ, Subramanian, N, Pero, ME, Bartolini, F, Amador, A, Kanber, A, Williams, D, Petri, S, Yang, M, Allen, AS, Beal, J, Haut, SR & Frankel, WN 2020, 'Arfgef1 haploinsufficiency in mice alters neuronal endosome composition and decreases membrane surface postsynaptic GABAA receptors', Neurobiology of Disease, vol. 134, 104632. https://doi.org/10.1016/j.nbd.2019.104632
Teoh, Jia Jie ; Subramanian, Narayan ; Pero, Maria Elena ; Bartolini, Francesca ; Amador, Ariadna ; Kanber, Ayla ; Williams, Damian ; Petri, Sabrina ; Yang, Mu ; Allen, Andrew S. ; Beal, Jules ; Haut, Sheryl R. ; Frankel, Wayne N. / Arfgef1 haploinsufficiency in mice alters neuronal endosome composition and decreases membrane surface postsynaptic GABAA receptors. In: Neurobiology of Disease. 2020 ; Vol. 134.
@article{0d29c701f55d473bbac4c67549c74036,
title = "Arfgef1 haploinsufficiency in mice alters neuronal endosome composition and decreases membrane surface postsynaptic GABAA receptors",
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.",
keywords = "Endocytic cycle, Epilepsy, GABA receptor, Lennox-Gastaut syndrome",
author = "Teoh, {Jia Jie} and Narayan Subramanian and Pero, {Maria Elena} and Francesca Bartolini and Ariadna Amador and Ayla Kanber and Damian Williams and Sabrina Petri and Mu Yang and Allen, {Andrew S.} and Jules Beal and Haut, {Sheryl R.} and Frankel, {Wayne N.}",
year = "2020",
month = "2",
doi = "10.1016/j.nbd.2019.104632",
language = "English (US)",
volume = "134",
journal = "Neurobiology of Disease",
issn = "0969-9961",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - Arfgef1 haploinsufficiency in mice alters neuronal endosome composition and decreases membrane surface postsynaptic GABAA receptors

AU - Teoh, Jia Jie

AU - Subramanian, Narayan

AU - Pero, Maria Elena

AU - Bartolini, Francesca

AU - Amador, Ariadna

AU - Kanber, Ayla

AU - Williams, Damian

AU - Petri, Sabrina

AU - Yang, Mu

AU - Allen, Andrew S.

AU - Beal, Jules

AU - Haut, Sheryl R.

AU - Frankel, Wayne N.

PY - 2020/2

Y1 - 2020/2

N2 - 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.

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 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.

KW - Endocytic cycle

KW - Epilepsy

KW - GABA receptor

KW - Lennox-Gastaut syndrome

UR - http://www.scopus.com/inward/record.url?scp=85074424806&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85074424806&partnerID=8YFLogxK

U2 - 10.1016/j.nbd.2019.104632

DO - 10.1016/j.nbd.2019.104632

M3 - Article

C2 - 31678406

AN - SCOPUS:85074424806

VL - 134

JO - Neurobiology of Disease

JF - Neurobiology of Disease

SN - 0969-9961

M1 - 104632

ER -