Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
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Drug
Enzyme
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Query: UMLS:C0036572 (
seizures
)
80,221
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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 GABA
A
receptors (GABA
A
R) are reduced in Arfgef1
fs/+
neurons with an accompanying decrease in the number of GABA
A
R-containing recycling endosomes in cell body. Arfgef1
fs/+
neurons also display differences in the relative ratio of Arf6
+
:Rab11
+
:TrfR
+
recycling endosomes. Although the GABA
A
R-containing early endosomes in Arfgef1
fs/+
neurons are comparable to wildtype, Arfgef1
fs/+
neurons show an increase in the number of GABA
A
R-containing lysosomes in dendrite and cell body. Together, the altered endosome composition and decreased neuronal surface GABA
A
R results suggests a mechanism whereby impaired neuronal inhibition leads to
seizure
susceptibility.
...
PMID:Arfgef1 haploinsufficiency in mice alters neuronal endosome composition and decreases membrane surface postsynaptic GABA
A
receptors. 3167 6
