Loss of IQSEC3 Disrupts GABAergic Synapse Maintenance and Decreases Somatostatin Expression in the Hippocampus

Seungjoon Kim, Hyeonho Kim, Dongseok Park, Jinhu Kim, Joohyeon Hong, Jae Seong Kim, Hyeji Jung, Dongwook Kim, Eunji Cheong, Jaewon Ko, Ji Won Um

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

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-GABAA 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.

Original languageEnglish
Pages (from-to)1995-2005.e5
JournalCell Reports
Volume30
Issue number6
DOIs
Publication statusPublished - 2020 Feb 11

Bibliographical note

Funding Information:
We are grateful to Dr. Hiroyuki Sakagami (Kitasato University, Japan) for kind gifts of IQSEC3 antibody and Jinha Kim for technical assistance. This study was supported by grants from the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT ( 2019R1H1A2079884 to J.W.U.) and the Brain Research Program through the NRF funded by the Ministry of Science, ICT & Future Planning ( 2017M3C7A1023470 to J. Ko and 2017M3C7A1023471 to E.C.).

Funding Information:
We are grateful to Dr. Hiroyuki Sakagami (Kitasato University, Japan) for kind gifts of IQSEC3 antibody and Jinha Kim for technical assistance. This study was supported by grants from the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (2019R1H1A2079884 to J.W.U.) and the Brain Research Program through the NRF funded by the Ministry of Science, ICT & Future Planning (2017M3C7A1023470 to J. Ko and 2017M3C7A1023471 to E.C.). J. Ko and J.W.U. conceived the project. S.K. H.K. D.P. J. Kim, J.H. J.S.K. H.J. and D.K. performed the experiments. S.K. H.K. D.P. J. Kim, J.H. E.C. J. Ko, and J.W.U. analyzed the data. E.C. J. Ko, and J.W.U. wrote the manuscript with input from the other authors. The authors declare no competing interests.

Publisher Copyright:
© 2020 The Author(s)

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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