PMID- 32049026
OWN - NLM
STAT- MEDLINE
DCOM- 20210308
LR  - 20210308
IS  - 2211-1247 (Electronic)
VI  - 30
IP  - 6
DP  - 2020 Feb 11
TI  - Loss of IQSEC3 Disrupts GABAergic Synapse Maintenance and Decreases Somatostatin 
      Expression in the Hippocampus.
PG  - 1995-2005.e5
LID - S2211-1247(20)30078-4 [pii]
LID - 10.1016/j.celrep.2020.01.053 [doi]
AB  - Gephyrin interacts with various GABAergic synaptic proteins to organize GABAergic 
      synapse development. Among the multitude of gephyrin-binding proteins is IQSEC3, 
      a recently identified component at GABAergic synapses that acts through its ADP 
      ribosylation factor-guanine nucleotide exchange factor (ARF-GEF) activity to 
      orchestrate GABAergic synapse formation. Here, we show that IQSEC3 knockdown (KD) 
      reduced GABAergic synaptic density in vivo, suggesting that IQSEC3 is required 
      for GABAergic synapse maintenance in vivo. We further show that IQSEC3 KD in the 
      dentate gyrus (DG) increases seizure susceptibility and triggers selective 
      depletion of somatostatin (SST) peptides in the DG hilus in an ARF-GEP 
      activity-dependent manner. Strikingly, selective introduction of SST into SST 
      interneurons in DG-specific IQSEC3-KD mice reverses GABAergic synaptic deficits. 
      Thus, our data suggest that IQSEC3 is required for linking gephyrin-GABA(A) 
      receptor complexes with ARF-dependent pathways to prevent aberrant, runaway 
      excitation and thereby contributes to the integrity of SST interneurons and 
      proper GABAergic synapse maintenance.
CI  - Copyright (c) 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
FAU - Kim, Seungjoon
AU  - Kim S
AD  - Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science 
      and Technology (DGIST), 333 Techno Jungangdae-Ro, Hyeonpoong-Eup, Dalseong-Gun, 
      Daegu 42988, Korea.
FAU - Kim, Hyeonho
AU  - Kim H
AD  - Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science 
      and Technology (DGIST), 333 Techno Jungangdae-Ro, Hyeonpoong-Eup, Dalseong-Gun, 
      Daegu 42988, Korea.
FAU - Park, Dongseok
AU  - Park D
AD  - Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science 
      and Technology (DGIST), 333 Techno Jungangdae-Ro, Hyeonpoong-Eup, Dalseong-Gun, 
      Daegu 42988, Korea.
FAU - Kim, Jinhu
AU  - Kim J
AD  - Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science 
      and Technology (DGIST), 333 Techno Jungangdae-Ro, Hyeonpoong-Eup, Dalseong-Gun, 
      Daegu 42988, Korea.
FAU - Hong, Joohyeon
AU  - Hong J
AD  - Department of Biotechnology, College of Life Science and Biotechnology, Yonsei 
      University, Seoul 03722, Korea.
FAU - Kim, Jae Seong
AU  - Kim JS
AD  - Department of Biotechnology, College of Life Science and Biotechnology, Yonsei 
      University, Seoul 03722, Korea.
FAU - Jung, Hyeji
AU  - Jung H
AD  - Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science 
      and Technology (DGIST), 333 Techno Jungangdae-Ro, Hyeonpoong-Eup, Dalseong-Gun, 
      Daegu 42988, Korea.
FAU - Kim, Dongwook
AU  - Kim D
AD  - Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science 
      and Technology (DGIST), 333 Techno Jungangdae-Ro, Hyeonpoong-Eup, Dalseong-Gun, 
      Daegu 42988, Korea.
FAU - Cheong, Eunji
AU  - Cheong E
AD  - Department of Biotechnology, College of Life Science and Biotechnology, Yonsei 
      University, Seoul 03722, Korea.
FAU - Ko, Jaewon
AU  - Ko J
AD  - Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science 
      and Technology (DGIST), 333 Techno Jungangdae-Ro, Hyeonpoong-Eup, Dalseong-Gun, 
      Daegu 42988, Korea. Electronic address: jaewonko@dgist.ac.kr.
FAU - Um, Ji Won
AU  - Um JW
AD  - Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science 
      and Technology (DGIST), 333 Techno Jungangdae-Ro, Hyeonpoong-Eup, Dalseong-Gun, 
      Daegu 42988, Korea; Core Protein Resources Center, DGIST, 333 Techno 
      Jungangdae-Ro, Hyeonpoong-Eup, Dalseong-Gun, Daegu 42988, Korea. Electronic 
      address: jiwonum@dgist.ac.kr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cell Rep
JT  - Cell reports
JID - 101573691
RN  - 0 (Guanine Nucleotide Exchange Factors)
RN  - 0 (IQSEC3 protein, human)
RN  - 0 (Iqsec3 protein, mouse)
RN  - 0 (Membrane Proteins)
RN  - 0 (gephyrin)
RN  - 51110-01-1 (Somatostatin)
SB  - IM
MH  - Animals
MH  - Guanine Nucleotide Exchange Factors/*deficiency/*metabolism
MH  - HEK293 Cells
MH  - Hippocampus/cytology/*metabolism
MH  - Humans
MH  - Male
MH  - Membrane Proteins/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Somatostatin/*metabolism
MH  - Synapses/*metabolism
OTO - NOTNLM
OT  - ARF6
OT  - GABA
OT  - IQSEC3
OT  - dentate gyrus
OT  - epilepsy
OT  - excitation-inhibition balance
OT  - gephyrin
OT  - inhibitory synapse
OT  - somatostatin
COIS- Declaration of Interests The authors declare no competing interests.
EDAT- 2020/02/13 06:00
MHDA- 2021/03/09 06:00
CRDT- 2020/02/13 06:00
PHST- 2019/09/13 00:00 [received]
PHST- 2019/12/28 00:00 [revised]
PHST- 2020/01/16 00:00 [accepted]
PHST- 2020/02/13 06:00 [entrez]
PHST- 2020/02/13 06:00 [pubmed]
PHST- 2021/03/09 06:00 [medline]
AID - S2211-1247(20)30078-4 [pii]
AID - 10.1016/j.celrep.2020.01.053 [doi]
PST - ppublish
SO  - Cell Rep. 2020 Feb 11;30(6):1995-2005.e5. doi: 10.1016/j.celrep.2020.01.053.