Nathanson, AJ;
Zhang, Y;
Smalley, JL;
Ollerhead, TA;
Santos, MAR;
Andrews, PM;
Wobst, HJ;
... Moss, SJ; + view all
(2019)
Identification of a Core Amino Acid Motif within the α Subunit of GABAᴀRs that Promotes Inhibitory Synaptogenesis and Resilience to Seizures.
Cell Reports
, 28
(3)
670-681.e8.
10.1016/j.celrep.2019.06.014.
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Abstract
The fidelity of inhibitory neurotransmission is dependent on the accumulation of γ-aminobutyric acid type A receptors (GABAARs) at the appropriate synaptic sites. Synaptic GABAARs are constructed from α(1-3), β(1-3), and γ2 subunits, and neurons can target these subtypes to specific synapses. Here, we identify a 15-amino acid inhibitory synapse targeting motif (ISTM) within the α2 subunit that promotes the association between GABAARs and the inhibitory scaffold proteins collybistin and gephyrin. Using mice in which the ISTM has been introduced into the α1 subunit (Gabra1-2 mice), we show that the ISTM is critical for axo-axonic synapse formation, the efficacy of GABAergic neurotransmission, and seizure sensitivity. The Gabra1-2 mutation rescues seizure-induced lethality in Gabra2-1 mice, which lack axo-axonic synapses due to the deletion of the ISTM from the α2 subunit. Taken together, our data demonstrate that the ISTM plays a critical role in promoting inhibitory synapse formation, both in the axonic and somatodendritic compartments.
| Type: | Article |
|---|---|
| Title: | Identification of a Core Amino Acid Motif within the α Subunit of GABAᴀRs that Promotes Inhibitory Synaptogenesis and Resilience to Seizures |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.celrep.2019.06.014 |
| Publisher version: | https://doi.org/10.1016/j.celrep.2019.06.014 |
| Language: | English |
| Additional information: | Copyright © 2019 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
| Keywords: | GABAA receptor, collybistin, gephyrin, axon initial segment, inhibition, epilepsy |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10080429 |
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