Npas4 regulates IQSEC3 expression in hippocampal somatostatin interneurons to mediate anxiety-like behavior

Seungjoon Kim; Dongseok Park; Jinhu Kim; Dongwook Kim; Hyeonho Kim; Takuma Mori; Hyeji Jung; Dongsu Lee; Sookyung Hong; Jongcheol Jeon; Katsuhiko Tabuchi; Eunji Cheong; Jaehoon Kim; Ji Won Um; Jaewon Ko

doi:10.1016/j.celrep.2021.109417

Npas4 regulates IQSEC3 expression in hippocampal somatostatin interneurons to mediate anxiety-like behavior

Seungjoon Kim, Dongseok Park, Jinhu Kim, Dongwook Kim, Hyeonho Kim, Takuma Mori, Hyeji Jung, Dongsu Lee, Sookyung Hong, Jongcheol Jeon, Katsuhiko Tabuchi, Eunji Cheong, Jaehoon Kim, Ji Won Um, Jaewon Ko

Research output: Contribution to journal › Article › peer-review

5 Citations (Scopus)

Abstract

Activity-dependent GABAergic synapse plasticity is important for normal brain functions, but the underlying molecular mechanisms remain incompletely understood. Here, we show that Npas4 (neuronal PAS-domain protein 4) transcriptionally regulates the expression of IQSEC3, a GABAergic synapse-specific guanine nucleotide-exchange factor for ADP-ribosylation factor (ARF-GEF) that directly interacts with gephyrin. Neuronal activation by an enriched environment induces Npas4-mediated upregulation of IQSEC3 protein specifically in CA1 stratum oriens layer somatostatin (SST)-expressing GABAergic interneurons. SST⁺ interneuron-specific knockout (KO) of Npas4 compromises synaptic transmission in these GABAergic interneurons, increases neuronal activity in CA1 pyramidal neurons, and reduces anxiety behavior, all of which are normalized by the expression of wild-type IQSEC3, but not a dominant-negative ARF-GEF-inactive mutant, in SST⁺ interneurons of Npas4-KO mice. Our results suggest that IQSEC3 is a key GABAergic synapse component that is directed by Npas4 and ARF activity, specifically in SST⁺ interneurons, to orchestrate excitation-to-inhibition balance and control anxiety-like behavior.

Original language	English
Article number	109417
Journal	Cell Reports
Volume	36
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2021.109417
Publication status	Published - 2021 Jul 20

Bibliographical note

Funding Information:
We are grateful to Jinha Kim (DGIST) for technical assistance and to Drs. Yingxi Lin (MIT, USA), Michael Greenberg (Harvard University, USA), Minmin Luo (Tsinghua University, China), and Hiroyuki Sakagami (Kitasato University, Japan) for kindly providing published reagents. This study was supported by grants from the Brain Research Program through the NRF funded by the Ministry of Science and ICT & Future Planning ( 2017M3C7A1023470 to Jaewon Ko; 2017M3C7A1023471 to E.C.; and 2019R1A2C1086048 and 2020R1A4A1019009 , to J.W.U.) and the DGIST R&D Program of the Ministry of Science and ICT ( 21-CoE-BT-01 to J.W.U. and Jaewon Ko).

Funding Information:
We are grateful to Jinha Kim (DGIST) for technical assistance and to Drs. Yingxi Lin (MIT, USA), Michael Greenberg (Harvard University, USA), Minmin Luo (Tsinghua University, China), and Hiroyuki Sakagami (Kitasato University, Japan) for kindly providing published reagents. This study was supported by grants from the Brain Research Program through the NRF funded by the Ministry of Science and ICT & Future Planning (2017M3C7A1023470 to Jaewon Ko; 2017M3C7A1023471 to E.C.; and 2019R1A2C1086048 and 2020R1A4A1019009, to J.W.U.) and the DGIST R&D Program of the Ministry of Science and ICT (21-CoE-BT-01 to J.W.U. and Jaewon Ko). J.W.U. and Jaewon Ko conceived and directed the project; S.K. D.P. Jinhu Kim, D.K. H.K. T.M. H.J. D.L. S.H. and J.J. performed the experiments; S.K. D.P. Jinhu Kim, T.M. K.T. E.C. Jaehoon Kim, J.W.U. and Jaewon Ko analyzed the data; and J.W.U. and Jaewon Ko wrote the manuscript. All of the authors read and commented on the manuscript. The authors declare no competing interests.

Publisher Copyright:
© 2021 The Authors

All Science Journal Classification (ASJC) codes

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.celrep.2021.109417

Cite this

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title = "Npas4 regulates IQSEC3 expression in hippocampal somatostatin interneurons to mediate anxiety-like behavior",

abstract = "Activity-dependent GABAergic synapse plasticity is important for normal brain functions, but the underlying molecular mechanisms remain incompletely understood. Here, we show that Npas4 (neuronal PAS-domain protein 4) transcriptionally regulates the expression of IQSEC3, a GABAergic synapse-specific guanine nucleotide-exchange factor for ADP-ribosylation factor (ARF-GEF) that directly interacts with gephyrin. Neuronal activation by an enriched environment induces Npas4-mediated upregulation of IQSEC3 protein specifically in CA1 stratum oriens layer somatostatin (SST)-expressing GABAergic interneurons. SST+ interneuron-specific knockout (KO) of Npas4 compromises synaptic transmission in these GABAergic interneurons, increases neuronal activity in CA1 pyramidal neurons, and reduces anxiety behavior, all of which are normalized by the expression of wild-type IQSEC3, but not a dominant-negative ARF-GEF-inactive mutant, in SST+ interneurons of Npas4-KO mice. Our results suggest that IQSEC3 is a key GABAergic synapse component that is directed by Npas4 and ARF activity, specifically in SST+ interneurons, to orchestrate excitation-to-inhibition balance and control anxiety-like behavior.",

author = "Seungjoon Kim and Dongseok Park and Jinhu Kim and Dongwook Kim and Hyeonho Kim and Takuma Mori and Hyeji Jung and Dongsu Lee and Sookyung Hong and Jongcheol Jeon and Katsuhiko Tabuchi and Eunji Cheong and Jaehoon Kim and Um, {Ji Won} and Jaewon Ko",

note = "Funding Information: We are grateful to Jinha Kim (DGIST) for technical assistance and to Drs. Yingxi Lin (MIT, USA), Michael Greenberg (Harvard University, USA), Minmin Luo (Tsinghua University, China), and Hiroyuki Sakagami (Kitasato University, Japan) for kindly providing published reagents. This study was supported by grants from the Brain Research Program through the NRF funded by the Ministry of Science and ICT & Future Planning ( 2017M3C7A1023470 to Jaewon Ko; 2017M3C7A1023471 to E.C.; and 2019R1A2C1086048 and 2020R1A4A1019009 , to J.W.U.) and the DGIST R&D Program of the Ministry of Science and ICT ( 21-CoE-BT-01 to J.W.U. and Jaewon Ko). Funding Information: We are grateful to Jinha Kim (DGIST) for technical assistance and to Drs. Yingxi Lin (MIT, USA), Michael Greenberg (Harvard University, USA), Minmin Luo (Tsinghua University, China), and Hiroyuki Sakagami (Kitasato University, Japan) for kindly providing published reagents. This study was supported by grants from the Brain Research Program through the NRF funded by the Ministry of Science and ICT & Future Planning (2017M3C7A1023470 to Jaewon Ko; 2017M3C7A1023471 to E.C.; and 2019R1A2C1086048 and 2020R1A4A1019009, to J.W.U.) and the DGIST R&D Program of the Ministry of Science and ICT (21-CoE-BT-01 to J.W.U. and Jaewon Ko). J.W.U. and Jaewon Ko conceived and directed the project; S.K. D.P. Jinhu Kim, D.K. H.K. T.M. H.J. D.L. S.H. and J.J. performed the experiments; S.K. D.P. Jinhu Kim, T.M. K.T. E.C. Jaehoon Kim, J.W.U. and Jaewon Ko analyzed the data; and J.W.U. and Jaewon Ko wrote the manuscript. All of the authors read and commented on the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

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day = "20",

doi = "10.1016/j.celrep.2021.109417",

language = "English",

volume = "36",

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T1 - Npas4 regulates IQSEC3 expression in hippocampal somatostatin interneurons to mediate anxiety-like behavior

AU - Kim, Seungjoon

AU - Park, Dongseok

AU - Kim, Jinhu

AU - Kim, Dongwook

AU - Kim, Hyeonho

AU - Mori, Takuma

AU - Jung, Hyeji

AU - Lee, Dongsu

AU - Hong, Sookyung

AU - Jeon, Jongcheol

AU - Tabuchi, Katsuhiko

AU - Cheong, Eunji

AU - Kim, Jaehoon

AU - Um, Ji Won

AU - Ko, Jaewon

N1 - Funding Information: We are grateful to Jinha Kim (DGIST) for technical assistance and to Drs. Yingxi Lin (MIT, USA), Michael Greenberg (Harvard University, USA), Minmin Luo (Tsinghua University, China), and Hiroyuki Sakagami (Kitasato University, Japan) for kindly providing published reagents. This study was supported by grants from the Brain Research Program through the NRF funded by the Ministry of Science and ICT & Future Planning ( 2017M3C7A1023470 to Jaewon Ko; 2017M3C7A1023471 to E.C.; and 2019R1A2C1086048 and 2020R1A4A1019009 , to J.W.U.) and the DGIST R&D Program of the Ministry of Science and ICT ( 21-CoE-BT-01 to J.W.U. and Jaewon Ko). Funding Information: We are grateful to Jinha Kim (DGIST) for technical assistance and to Drs. Yingxi Lin (MIT, USA), Michael Greenberg (Harvard University, USA), Minmin Luo (Tsinghua University, China), and Hiroyuki Sakagami (Kitasato University, Japan) for kindly providing published reagents. This study was supported by grants from the Brain Research Program through the NRF funded by the Ministry of Science and ICT & Future Planning (2017M3C7A1023470 to Jaewon Ko; 2017M3C7A1023471 to E.C.; and 2019R1A2C1086048 and 2020R1A4A1019009, to J.W.U.) and the DGIST R&D Program of the Ministry of Science and ICT (21-CoE-BT-01 to J.W.U. and Jaewon Ko). J.W.U. and Jaewon Ko conceived and directed the project; S.K. D.P. Jinhu Kim, D.K. H.K. T.M. H.J. D.L. S.H. and J.J. performed the experiments; S.K. D.P. Jinhu Kim, T.M. K.T. E.C. Jaehoon Kim, J.W.U. and Jaewon Ko analyzed the data; and J.W.U. and Jaewon Ko wrote the manuscript. All of the authors read and commented on the manuscript. The authors declare no competing interests. Publisher Copyright: © 2021 The Authors

PY - 2021/7/20

Y1 - 2021/7/20

N2 - Activity-dependent GABAergic synapse plasticity is important for normal brain functions, but the underlying molecular mechanisms remain incompletely understood. Here, we show that Npas4 (neuronal PAS-domain protein 4) transcriptionally regulates the expression of IQSEC3, a GABAergic synapse-specific guanine nucleotide-exchange factor for ADP-ribosylation factor (ARF-GEF) that directly interacts with gephyrin. Neuronal activation by an enriched environment induces Npas4-mediated upregulation of IQSEC3 protein specifically in CA1 stratum oriens layer somatostatin (SST)-expressing GABAergic interneurons. SST+ interneuron-specific knockout (KO) of Npas4 compromises synaptic transmission in these GABAergic interneurons, increases neuronal activity in CA1 pyramidal neurons, and reduces anxiety behavior, all of which are normalized by the expression of wild-type IQSEC3, but not a dominant-negative ARF-GEF-inactive mutant, in SST+ interneurons of Npas4-KO mice. Our results suggest that IQSEC3 is a key GABAergic synapse component that is directed by Npas4 and ARF activity, specifically in SST+ interneurons, to orchestrate excitation-to-inhibition balance and control anxiety-like behavior.

AB - Activity-dependent GABAergic synapse plasticity is important for normal brain functions, but the underlying molecular mechanisms remain incompletely understood. Here, we show that Npas4 (neuronal PAS-domain protein 4) transcriptionally regulates the expression of IQSEC3, a GABAergic synapse-specific guanine nucleotide-exchange factor for ADP-ribosylation factor (ARF-GEF) that directly interacts with gephyrin. Neuronal activation by an enriched environment induces Npas4-mediated upregulation of IQSEC3 protein specifically in CA1 stratum oriens layer somatostatin (SST)-expressing GABAergic interneurons. SST+ interneuron-specific knockout (KO) of Npas4 compromises synaptic transmission in these GABAergic interneurons, increases neuronal activity in CA1 pyramidal neurons, and reduces anxiety behavior, all of which are normalized by the expression of wild-type IQSEC3, but not a dominant-negative ARF-GEF-inactive mutant, in SST+ interneurons of Npas4-KO mice. Our results suggest that IQSEC3 is a key GABAergic synapse component that is directed by Npas4 and ARF activity, specifically in SST+ interneurons, to orchestrate excitation-to-inhibition balance and control anxiety-like behavior.

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Npas4 regulates IQSEC3 expression in hippocampal somatostatin interneurons to mediate anxiety-like behavior

Abstract

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