Finding the Clue: How a Specific Synapse Type Regulates Anxiety-like Behavior

Experiments conducted on genetically modified mice clarify the role of a protein in regulating properties of specific hippocampal neural circuits

Part of the research team at the Department of Brain and Cognitive Sciences at DGIST. Clockwise from the back-left are Professor Ji Won Um, Professor Jaewon Ko, and Master’s and Doctorate integrated students Seungjoon Kim, Jinhu Kim, and Dongseok Park.

The chemicals, proteins, and genes involved in the development and functioning of synapses vary across different neuron types and brain regions, making it very challenging to pinpoint the specific function each of them plays.

The mechanisms behind the organization of neuronal synapses remain unclear owing to the sheer number of genes, proteins, and neuron types involved. In a recent study, Daegu Gyeongbuk Institute of Science and Technology scientists conducted a series of experiments in genetically modified mice to clarify the role of two proteins in regulating the development of inhibitory synapses in the hippocampus, in the context of anxiety-related behaviors, paving the way to better understand the brain.

The correct functioning of our brain, as well as that of other animals, depends on a very intricate interplay between multiple types of neurons. These interactions are orchestrated by multitudes of synaptic proteins; thus, pinpointing their specific functions is extremely challenging. In particular, the molecular mechanisms that regulate the plasticity of synapses are not completely understood.

Synapse plasticity is crucial for animals to correctly respond and adapt to their environment at the behavioral level. Over the past decade, several studies have focused on two proteins that are related to synapses mediated by GABA, the most important inhibitory neurotransmitter in mammals. Npas4, the first of the two, is closely related to shaping inhibitory synapse organization, but it fulfills many different roles across various brain regions. Contrarily, IQSEC3, the second protein, is exclusively found in ‘GABAergic’ synapses and is believed to be a target of Npas4, though this has not been conclusively demonstrated in live animals. Now, in a recent study published in Cell Reports, a team of scientists from Daegu Gyeongbuk Institute of Science and Technology (DGIST), Korea, report findings of their study on mice that shed light on the specific functions of Npas4 and IQSEC3 in a specific brain region, called the hippocampus.

First, both in neuronal cell cultures and in mice, the scientists demonstrated that Npas4 promotes the expression of IQSEC3 and, most importantly, facilitates the organization of GABAergic synapses in a specific synapse of hippocampal neurons. Then, through behavioral experiments and subsequent chemogenetic approaches applied on genetically modified mice, the scientists observed that the specific GABAergic synapses organized by Npas4 and IQSEC3 are directly linked to anxiety-like behaviors. More specifically, mice with dysregulated IQSEC3 expression responded differently from control mice in experimental scenarios that would normally induce anxiety-related responses. “Our research may help us understand how abnormalities in anxiety-like behavior occur and design circuit-based therapeutic approaches for correcting them,” remarks Professor Ji Won Um from the Department of Brain and Cognitive Sciences at DGIST, who led the study.         

The team plans to continue investigating the role of IQSEC3 in different type of synapses and neural circuits using even more sophisticated genetic approaches. Clarifying the molecular mechanisms of the brain will surely pave the way to breakthroughs in brain medicine, as Dr. Um explains: “Understanding synapses is instrumental in grasping the pathogenesis of neuropsychiatric and neurodevelopmental disorders because various forms of synaptic dysfunctions occur in such diseases. Thus, basic neuroscience research is unquestionably essential for making progress in this regard.

Let us hope further studies add more pieces to the gigantic puzzle that is comprehending the brain.

Reference

Authors:

Seungjoon Kim,1 Dongseok Park,1 Jinhu Kim,1 Dongwook Kim,1 Hyeonho Kim,1 Takuma Mori,2 Hyeji Jung,1 Dongsu Lee,3 Sookyung Hong,4 Jongcheol Jeon,4 Katsuhiko Tabuchi,2,5 Eunji Cheong,3 Jaehoon Kim,4 Ji Won Um,1* and Jaewon Ko1,*

Title of original paper:

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

Journal:

Cell Reports

DOI:

10.1016/j.celrep.2021.109417

Affiliations:

1Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST)

2Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University

3Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University

4Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST)

5Department of Molecular and Cellular Physiology, Institute of Medicine, Academic Assembly, Shinshu University

 

*Corresponding authors’ emails: [email protected] (J.W.U.), [email protected] (J.K.)

About Daegu Gyeongbuk Institute of Science and Technology (DGIST)

Daegu Gyeongbuk Institute of Science and Technology (DGIST) is a well-known and respected research institute located in Daegu, Republic of Korea. Established in 2004 by the Korean Government, the main aim of DGIST is to promote national science and technology, as well as to boost the local economy.

With a vision of “Changing the world through convergence", DGIST has undertaken a wide range of research in various fields of science and technology. DGIST has embraced a multidisciplinary approach to research and undertaken intensive studies in some of today's most vital fields. DGIST also has state-of-the-art-infrastructure to enable cutting-edge research in materials science, robotics, cognitive sciences, and communication engineering.

Website:   https://www.dgist.ac.kr/en/html/sub01/010204.html

About the author

Ji Won Um joined the Department of Brain and Cognitive Sciences at DGIST as an Associate Professor in 2017. She obtained B.S., M.S. and PhD degrees in Biology from Yonsei University, Korea, in 2002, 2004, and 2008, respectively. She underwent postdoctoral research training in Yale University School of Medicine in the USA. She worked as an assistant professor at Yonsei University College of Medicine from 2015 before joining DGIST. Since 2019, she has also been working as Adjunct Professor in the Core Protein Resources Center at DGIST. Her interests lie in the key pathophysiological mechanisms of synaptic disorders, including Alzheimer’s disease, autism spectrum disorder, and epilepsy. Dr. Um has published over 50 peer-reviewed papers.

Published: 12 Aug 2021

Contact details:

Nari Kim

333, Techno jungang-daero, Hyeonpung-myeon, Dalseong-gun, Daegu, 42988

+82-53-785-1135
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Authors:
Seungjoon Kim,1 Dongseok Park,1 Jinhu Kim,1 Dongwook Kim,1 Hyeonho Kim,1 Takuma Mori,2 Hyeji Jung,1 Dongsu Lee,3 Sookyung Hong,4 Jongcheol Jeon,4 Katsuhiko Tabuchi,2,5 Eunji Cheong,3 Jaehoon Kim,4 Ji Won Um,1* and Jaewon Ko1,*

Title of original paper:
Npas4 regulates IQSEC3 expression in hippocampal somatostatin interneurons to mediate anxiety-like behavior

Journal: Cell Reports

DOI: https://doi.org/10.1016/j.celrep.2021.109417

Affiliations:
1 Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST)

2 Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University

3 Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University

4 Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST)

5 Department of Molecular and Cellular Physiology, Institute of Medicine, Academic Assembly, Shinshu University