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O‐GlcNAc Transferase OGT‐1 and the Ubiquitin Ligase EEL‐1 Modulate Seizure Susceptibility in C. elegans
Author(s) -
Suthakaran Nirthieca,
Wiggins Jonathan,
Giles Andrew,
Opperman Karla,
DawsonScully Ken,
Grill Brock
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.01915
Subject(s) - gabaergic , neurotransmission , ubiquitin ligase , inhibitory postsynaptic potential , biology , gamma aminobutyric acid , neuroscience , caenorhabditis elegans , nervous system , acetylcholine , mutant , microbiology and biotechnology , receptor , ubiquitin , biochemistry , pharmacology , gene
Neurodevelopmental disorders such as autism and epilepsy have been linked to an imbalance of excitation and inhibition (E/I) in the central nervous system. The simplicity and tractability of C. elegans allows our electroconvulsive seizure (ES) assay to be used as a behavioral readout of the locomotor circuit and neuronal function. C. elegans possess conserved nervous system features such as gamma‐aminobutyric acid (GABA) and GABA receptors in inhibitory neurotransmission, and acetylcholine (Ach) and acetylcholine receptors in excitatory neurotransmission. Our previously published data has shown that decreasing inhibition in the motor circuit, via GABAergic manipulation, will extend the time of locomotor recovery following ES. Similarly, mutations in a HECT E3 ubiquitin ligase called EEL‐1 leads to impaired GABAergic transmission, E/I imbalance and altered sensitivity to ES. Mutations in the human ortholog of EEL‐1, called HUWE1, are associated with both syndromic and non‐syndromic intellectual disability. Both EEL‐1 and its previously established binding protein, OGT‐1, are expressed in GABAergic motor neurons, localize to GABAergic presynaptic terminals, and function in parallel to regulate GABA neuron function. In this study, we tested behavioral responses to ES in wildtype, ogt‐1 , eel‐1 and ogt‐1; eel‐1 double mutants. Both single null mutants of OGT‐1 and EEL‐1 proteins have decreased inhibitory GABAergic neuron function and increased ES sensitivity. Consistent with EEL‐1 and OGT‐1 functioning in parallel pathways, ogt‐1; eel‐1 double mutants showed enhanced ES susceptibility. Expression of OGT‐1 in the C. elegans nervous system rescued enhanced ES defects in ogt‐1; eel‐1 double mutants. Our C. elegans ES seizure assay was first to model a human X‐linked Intellectual Disorder (XLID) associated with epilepsy and suggests a potential novel role for the OGT‐1/EEL‐1 complex in seizure susceptibility.