Document Type
Article
Publication Date
7-16-2019
Publication Title
Cell Reports
Publisher
Elsevier
Volume
28
Issue
3
First page number:
670
Last page number:
681
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.
Keywords
GABAA receptor; Collybistin; Gephyrin; Axon initial segment; Inhibition; Epilepsy
Disciplines
Neuroscience and Neurobiology | Psychology
File Format
File Size
4.031 KB
Language
English
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License
Repository Citation
Nathanson, A. J.,
Zhang, Y.,
Smalley, J. L.,
Ollerhead, T. A.,
Rodriguez Santos, M. A.,
Andrews, P. M.,
Wobst, H. J.,
Moore, Y. E.,
Brandon, N. J.,
Hines, R. M.,
Davies, P. A.,
Moss, S. J.
(2019).
Identification of a Core Amino Acid Motif within the α Subunit of GABAARs that Promotes Inhibitory Synaptogenesis and Resilience to Seizures.
Cell Reports, 28(3),
670-681.
Elsevier.
http://dx.doi.org/10.1016/j.celrep.2019.06.014