Identification of a Core Amino Acid Motif within the α Subunit of GABAARs that Promotes Inhibitory Synaptogenesis and Resilience to Seizures

Cell Rep. 2019 Jul 16;28(3):670-681.e8. doi: 10.1016/j.celrep.2019.06.014.

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: GABA(A) receptor; axon initial segment; collybistin; epilepsy; gephyrin; inhibition.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Motifs / genetics*
  • Animals
  • Axons / metabolism*
  • Axons / physiology
  • Cells, Cultured
  • GABAergic Neurons / metabolism*
  • GABAergic Neurons / physiology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / metabolism*
  • Rho Guanine Nucleotide Exchange Factors / genetics
  • Rho Guanine Nucleotide Exchange Factors / metabolism
  • Seizures / genetics
  • Seizures / metabolism*
  • Seizures / mortality
  • Synapses / genetics
  • Synapses / metabolism*
  • Synaptic Transmission / physiology

Substances

  • Arhgef9 protein, mouse
  • Gabra2 protein, mouse
  • Membrane Proteins
  • Receptors, GABA-A
  • Rho Guanine Nucleotide Exchange Factors
  • gephyrin