Molecular targets of volatile anesthetics isoflurane at the calyx of Held synapse.

• Project/Area Number: 18K16467
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55050:Anesthesiology-related
• Research Institution: Okinawa Institute of Science and Technology Graduate University
• Principal Investigator: WANG HAN-YING 沖縄科学技術大学院大学, 細胞分子シナプス機能ユニット, 研究員 (70814333)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: Isoflurane / calyx of Held / capacitance measurement / exo-endocytosis / neurotransmission / Calyx of Held / Cerebral cortex / Presynaptic reocrding / Capacitance / Action potential / exocytic machinery / Ion channels / Fidelity

Outline of Final Research Achievements

Synaptic mechanisms of general anesthesia remain unidentified. In rat brainstem slices, isoflurane inhibits excitatory transmitter release by blocking presynaptic calcium channels and exocytic machinery, with the latter mechanism predominating in its inhibitory effect on high-frequency transmission. Both in slice and in vivo, isoflurane preferentially inhibits spike transmission induced by high-frequency presynaptic inputs. This low-pass filtering action of isoflurane likely plays a significant role in general anesthesia.

Academic Significance and Societal Importance of the Research Achievements

We discovered isoflurane preferentially inhibits high-frequency neurotransmission, therefore, selective inhibition by volatile anesthetics of high-frequency transmission will effectively attenuate such integral neuronal functions, with minimal inhibition of basal neuronal functions.

Research Products

• [Journal Article] Frequency-Dependent Block of Excitatory Neurotransmission by Isoflurane via Dual Presynaptic Mechanisms. (2020)
  • Author(s): Wang HY, Eguchi K, Yamashita T, Takahashi T.
  • Journal Title: Journal of Neuroscience Volume: 40 Issue: 21 Pages: 4103-4115
  • DOI: 10.1523/jneurosci.2946-19.2020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Presynaptic Inhibitory Mechanism of the Volatile Anesthetics Isoflurane. (2018)
  • Author(s): Han-Ying Wang, Kohgaku Eguchi, Tomoyuki Takahashi
  • Organizer: The 41st Annual Meeting of the Japan Neuroscience Society
  • Int'l Joint Research
• [Presentation] Isoflurane preferentially inhibits high-frequency excitatory neurotransmission via directly inhibiting vesicle fusion mechanism. (2018)
  • Author(s): Han-Ying Wang, Kohgaku Eguchi, Tomoyuki Takahashi
  • Organizer: Society for Neuroscience - Neuroscience 2018
  • Int'l Joint Research