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 journalArticle

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

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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    Kim, S., Kim, H., Park, D., Kim, J., Hong, J., Kim, J. S., Jung, H., Kim, D., Cheong, E., Ko, J., & Um, J. W. (2020). Loss of IQSEC3 Disrupts GABAergic Synapse Maintenance and Decreases Somatostatin Expression in the Hippocampus. Cell Reports, 30(6), 1995-2005.e5. https://doi.org/10.1016/j.celrep.2020.01.053