Molecular mechanisms that regulate the sensory experience-dependent development of dendritic spines in newborn olfactory bulb interneurons

• Project/Area Number: 25290015
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Nara Medical University
• Principal Investigator: Tsuboi Akio 奈良県立医科大学, 医学部, 教授 (20163868)
• Co-Investigator(Kenkyū-buntansha): YOSHIHARA SEIICHI 奈良県立医科大学, 医学部, 講師 (90360669) ; TAKAHASHI HIROO 奈良県立医科大学, 医学部, 助教 (20390685)
• Co-Investigator(Renkei-kenkyūsha): KOMAI SHOUJI 奈良先端科学技術大学院大学, バイオサイエンス研究科, 准教授 (50420469)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000); Fiscal Year 2015: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2014: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
• Keywords: 成体神経新生 / 嗅球介在ニューロン / 神経活動依存性 / 神経可塑性 / 神経再生 / 嗅覚系

Outline of Final Research Achievements

Sensory experience regulates neuronal development in various brain structures, including the cortex, hippocampus and olfactory bulb (OB). However, little is known about the developmental role of sensory experience in major OB populations of inhibitory interneurons, such as granule cells (GCs). In this study, we identified a transcription factor Npas4 gene, which is expressed in a subset of OB GCs following sensory experience. Npas4 overexpression in newborn OB GCs increased the spine density even under sensory deprivation. Conversely, Npas4-KO mice resulted in a significant reduction in the spine density of OB GCs. Furthermore, we identified, as a novel target of Npas4, an E3 ubiquitin ligase Mdm2 gene, which is expressed at low levels in the wild-type OB but at higher levels in the Npas4-KO OB. These results suggest that Npas4 regulates Mdm2 expression to ubiquitinate and degrade a microtubule-associated protein Dcx for shaping the dendritic spines of OB GCs after sensory experience.

Research Products

• [Int'l Joint Research] University of Manchester(United Kingdom)
• [Int'l Joint Research] Kantonsspital Aarau(Switzerland)
• [Journal Article] Transcription factor Npas4 regulates the development of dendritic spines in newborn olfactory bulb interneurons depending on sensory experience (2016)
  • Author(s): 吉原誠一，坪井昭夫
  • Journal Title: 生化学 Volume: 88 Issue: 2 Pages: 220-224
  • DOI: 10.14952/SEIKAGAKU.2016.880220
  • NAID: 40020843392
  • ISSN: 0037-1017
  • Year and Date: 2016-04-25
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Evaluation of a filament perforation model for mouse subarachnoid hemorrhage using 7.0 Tesla MRI (2016)
  • Author(s): Muroi C, Kashiwagi Y, Rokugawa T, Tonomura M, Obata A, Nevzati E, Tsuboi A, Okuchi K, Mishima K, Abe K, Fujioka M
  • Journal Title: J Clin Neurosci. Volume: 28 Pages: 141-147
  • DOI: 10.1016/j.jocn.2015.10.045
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Molecular mechanisms regulating the dendritic development of newborn olfactory bulb interneurons in a sensory experience-dependent manner. (2016)
  • Author(s): Yoshihara S, Takahashi H and Tsuboi A.
  • Journal Title: Frontiers in Neuroscience Volume: 9 Pages: 514-514
  • DOI: 10.3389/fnins.2015.00514
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Supersensitive odor discrimination is controlled in part by initial transient interactions between the most sensitive dorsal olfactory receptors and G-proteins (2016)
  • Author(s): Sato T, Kobayakawa R, Kobayakawa K, Emura M, Itohara S, Kawasaki T, Tsuboi A, Matsumura H
  • Journal Title: Receptors & Clinical Investigation Volume: 3
  • DOI: 10.14800/rci.1117
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Supersensitive detection and discrimination of enantiomers by dorsal olfactory receptors: evidence for hierarchical odour coding (2015)
  • Author(s): Sato T, Kobayakawa R, Kobayakawa K, Emura M, Itohara S, Kizumi M, Hamana H, Tsuboi A, Hirono J
  • Journal Title: Scientific Reports Volume: 5 Issue: 1 Pages: 14073-14073
  • DOI: 10.1038/srep14073
  • Peer Reviewed / Open Access
• [Journal Article] 嗅覚系におけるCO2センシングの分子機構 (2015)
  • Author(s): 高橋弘雄，坪井昭夫
  • Journal Title: におい・かおり環境学会誌 Volume: 46 Pages: 209-217
  • NAID: 130007602381
  • Peer Reviewed
• [Journal Article] Npas4 regulates Mdm2 and thus Dcx in experience-dependent olfactory bulb interneuron dendritic spine development. (2014)
  • Author(s): Yoshihara S, Takahashi H, Nishimura N, Kinoshita M, Asahina R, Kitsuki M, Tatsumi K, Furukawa-Hibi Y, Hirai H, Nagai T, Yamada K and Tsuboi A.
  • Journal Title: Cell Reports Volume: 8 Issue: 3 Pages: 843-857
  • DOI: 10.1016/j.celrep.2014.06.056
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 嗅球ニューロンにおける匂い刺激依存的なシナプス形成の分子機構 (2014)
  • Author(s): 吉原誠一，高橋弘雄，坪井昭夫
  • Journal Title: Aroma Research Volume: 15 Pages: 248-249
• [Journal Article] 嗅覚系におけCO2センシングの分子機構 (2013)
  • Author(s): 高橋弘雄、坪井昭夫
  • Journal Title: 化学と生物 Volume: 51 Pages: 437-439
  • Peer Reviewed
• [Presentation] A specific subtype of olfactory bulb interneurons is necessary for odor detection and odor-background segregation (2016)
  • Author(s): Takahashi H, Yoshihara S, Ogawa Y, Asahina R, Kitano T, Tsuboi A
  • Organizer: The 17th International Symposium on Olfaction and Taste (ISOT 2016)
  • Place of Presentation: Yokohama (Japan)
  • Year and Date: 2016-06-05
  • Int'l Joint Research / Invited
• [Presentation] A specific subtype of newborn interneurons in the olfactory bulb is required for behaviors on odor detection and discrimination (2016)
  • Author(s): Takahashi H, Yoshihara S, Ogawa Y, Asahina R, Kinoshita M, Tsuboi A
  • Organizer: Conference on Neurogenesis 2016: Implications for Lifelong Development and Disease
  • Place of Presentation: Cancun (Mexico)
  • Year and Date: 2016-03-02
  • Int'l Joint Research
• [Presentation] A specific subtype of adult-born interneurons in the olfactory bulb is required for behaviors on odor detection and discrimination (2015)
  • Author(s): Tsuboi A, Yoshihara S, Ogawa Y, Asahina R, Kinoshita M, Takahashi H
  • Organizer: Current Trends in Biomedicine 2015: Development and Adult Neurogenesis in the Central Nervous System
  • Place of Presentation: Baeza (Spain)
  • Year and Date: 2015-10-05
  • Int'l Joint Research / Invited
• [Presentation] A specific subtype of newborn interneurons in the olfactory bulb play a crucial role in odor detection and discrimination (2015)
  • Author(s): Tsuboi A, Takahashi H, Yoshihara S, Ogawa Y, Stern PL
  • Organizer: The 2015 Bridging Biomedical Worlds Symposium: From Neural Circuitry to Neurotechnology
  • Place of Presentation: Tokyo (Japan)
  • Year and Date: 2015-05-11
  • Int'l Joint Research
• [Presentation] Transcription factor Npas4 regulates the sensory experience-dependent development of dendritic spines in newborn olfactory bulb interneurons (2015)
  • Author(s): 吉原誠一，高橋弘雄，西村信城，木下雅仁，朝比奈諒，日比陽子，永井拓，山田清文，坪井昭夫
  • Organizer: 第92回日本生理学会大会
  • Place of Presentation: 神戸コンベンションセンター（神戸市中央区港島中町）
  • Year and Date: 2015-03-21 – 2015-03-23
• [Presentation] 5T4 oncofetal trophoblast glycoprotein regulates the sensory experience- (2015)
  • Author(s): 高橋弘雄，吉原誠一，小川陽一，朝比奈諒，玉田喜規，坪井昭夫
  • Organizer: 第92回日本生理学会大会
  • Place of Presentation: 神戸コンベンションセンター（神戸市中央区港島中町）
  • Year and Date: 2015-03-21 – 2015-03-23
• [Presentation] Transcription factor Npas4 regulates the sensory experience-dependent development of dendritic spines in newborn olfactory bulb interneurons (2014)
  • Author(s): 吉原誠一，高橋弘雄，西村信城，木下雅仁，朝比奈諒，日比陽子，永井拓，山田清文，坪井昭夫
  • Organizer: 第37回日本分子生物学会大会
  • Place of Presentation: パシフィコ横浜（横浜市西区みなとみらい）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] 5T4 oncofetal trophoblast glycoprotein regulates the sensory experience-dependent dendritic development of olfactory bulb interneurons (2014)
  • Author(s): 高橋弘雄，吉原誠一，小川陽一，朝比奈諒，玉田喜規，坪井昭夫
  • Organizer: 第37回日本分子生物学会大会
  • Place of Presentation: パシフィコ横浜（横浜市西区みなとみらい）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] Transcription factor Npas4 regulates the sensory experience-dependent development of dendritic spines in newborn olfactory bulb interneurons (2014)
  • Author(s): Takahashi H, Yoshihara S, Nishimura N, Kinoshita M, Asahina R, Furukawa-Hibi Y, Nagai T, Yamada K, Tsuboi A
  • Organizer: The 12th International Symposium on Molecular and Neural Mechanisms of Taste and Olfactory Perception
  • Place of Presentation: Kyushu University, Fukuoka, Japan
  • Year and Date: 2014-11-02 – 2014-11-03
  • Invited
• [Presentation] Transcription factor Npas4 regulates the sensory experience-dependent development of dendritic spines in newborn olfactory bulb interneurons (2014)
  • Author(s): Takahashi H, Yoshihara S, Nishimura N, Kinoshita M, Asahina R, Furukawa-Hibi Y, Nagai T, Yamada K, Tsuboi A
  • Organizer: Cold Spring Harbor Meeting: Axon Guidance, Synapse Formation & Regeneration
  • Place of Presentation: Cold Spring Harbor, USA
  • Year and Date: 2014-09-16 – 2014-09-20
• [Presentation] Transcription factor Npas4 regulates the sensory experience-dependent development of dendritic spines in newborn olfactory bulb interneurons (2014)
  • Author(s): 吉原誠一，高橋弘雄，西村信城，木下雅仁，朝比奈諒，日比陽子，永井拓，山田清文，坪井昭夫
  • Organizer: 第37回日本神経科学会大会
  • Place of Presentation: パシフィコ横浜（横浜市西区みなとみらい）
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] 5T4 glycoprotein regulates the sensory experience-dependent dendritic development of olfactory bulb interneurons (2014)
  • Author(s): 高橋弘雄，吉原誠一，小川陽一，西村信城，木下雅仁，玉田喜規，坪井昭夫
  • Organizer: 第37回日本神経科学会大会
  • Place of Presentation: パシフィコ横浜（横浜市西区みなとみらい）
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] 5T4 and Npas4 regulate the sensory experience-dependent development of dendrites in newborn olfactory bulb interneurons (2014)
  • Author(s): Tsuboi A, Takahashi H, Asahina R, Kinoshita M, Nishimura N, Yoshihara S
  • Organizer: Keystone Symposia: Adult Neurogenesis
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2014-05-12 – 2014-05-17
• [Presentation] Transcription factor Npas4 regulates the sensory experience-dependent development of dendritic spines in newborn olfactory bulb interneurons (2014)
  • Author(s): Yoshihara S, Takahashi H, Nishimura N, Kinoshita M, Asahina R, Furukawa-Hibi Y, Nagai T, Yamada K, Tsuboi A
  • Organizer: Cold Spring Harbor Meeting: Neuronal Circuits
  • Place of Presentation: Cold Spring Harbor, USA
  • Year and Date: 2014-04-02 – 2014-04-05
• [Presentation] Npas4 regulates the sensory experience-dependent development of dendritic spines in newborn olfactory bulb interneuron. (2014)
  • Author(s): Yoshihara S, Takahashi H, Nishimura N, Kinoshita M, Asahina R, Furukawa-Hibi Y, Nagai T, Yamada K and Tsuboi A
  • Organizer: Cold Spring Harbor Meeting: Neuronal Circuits
  • Place of Presentation: Cold Spring Harbor, USA
• [Presentation] 5T4 and Npas4 regulate the sensory experience-dependent development of dendrites in newborn olfactory bulb interneurons. (2014)
  • Author(s): Tsuboi A, Takahashi H, Asahina R, Kinoshita M, Nishimura N and Yoshihara S
  • Organizer: Keystone Symposia: Adult Neurogenesis
  • Place of Presentation: Stockholm, Sweden
• [Presentation] Npas4 transcription factor regulates the sensory experience-dependent dendritic spine development of newborn interneurons in the mouse olfactory bulb. (2013)
  • Author(s): Tsuboi A, Takahashi H, Kinoshita M, Nishimura N and Yoshihara S.
  • Organizer: Cell Symposia: Genes, Circuits & Behaviour
  • Place of Presentation: Toronto, Canada
• [Presentation] Npas4 regulates sensory experience-dependent development of dendritic spines in olfactory bulb granule cells. (2013)
  • Author(s): Yoshihara S, Takahashi H, Kinoshita M, Nishimura N Nagai T, Yamada K and Tsuboi A
  • Organizer: Neurogenesis 2013 in Matsushima
  • Place of Presentation: Miyagi, Japan
• [Book] Electroporation Methods in Neuroscience (Neuromethods) (2015)
  • Author(s): Takahashi H, Yoshihara S, Asahina R, Tamada Y, Tsuboi A
  • Total Pages: 11
  • Publisher: Springer
• [Book] Handbook of Olfaction and Gustation, Third Edition (2015)
  • Author(s): Tsuboi A, Sakano H
  • Total Pages: 10
  • Publisher: Wiley-Blackwell
• [Book] Electroporation Methods in Neuroscience, Neuromethods 102 (Springer) (2015)
  • Author(s): Takahashi H, Yoshihara S, Asahina R, Tamada Y, Tsuboi A
  • Total Pages: 11
  • Publisher: Characterization of newborn interneurons in the mouse olfactory bulb using postnatal electroporation
• [Book] Handbook of Olfaction & Gustation (3rd edition): Modern Perspectives (editor, Doty, R.L.) (2014)
  • Author(s): Tsuboi A and Sakano H
  • Total Pages: 1250
  • Publisher: Wiley-Blackwell Publishing
• [Remarks] ＨＯＭＥ（脳神経システム医科学）
  • URL: http://www.naramed-u.ac.jp/~amrc-lab1/
• [Remarks] 奈良県立医科大学 先端医学研究機構 脳神経システム医科学
  • URL: http://www.naramed-u.ac.jp/~amrc-lab1/
• [Remarks] 奈良県立医科大学 先端医学研究機構 脳神経システム医科学
  • URL: http://www.naramed-u.ac.jp/~amrc-lab1/