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Synaptic regulation in the cerebellum and motor control

開催日 2014/9/11
時間 9:00 - 11:00
会場 Room E(301)
Chairperson(s) 平井 宏和 / Hirokazu Hirai (群馬大学大学院医学系研究科神経生理学分野 / Department of Neurophysiology, Gunma University Graduate School of Medicine, Japan)
平野 丈夫 / Tomoo Hirano (京都大学理学研究科 生物物理 / Department of Biophysics, Graduate School of Science, Kyoto University, Japan)

Understanding both enhanced and impaired learning with enhanced plasticity: a saturation hypothesis

  • S1-E-1-2
  • Jennifer Raymond:1 T.D. Barbar Nguyen-Vu:1 Grace Q. Zhao:1 Subhaneil Lahiri: Aparna Suvrathan: Hanmi Lee: Surya Ganguli: Carla J. Shatz: 
  • 1:Stanford University School of Medicine, USA 

Transgenic mice with enhanced long-term potentiation (LTP) or long-term depression (LTD) sometimes exhibit enhanced learning, but, paradoxically, often exhibit impaired learning. Here, we show that mice deficient in the Class-I major histocompatibility molecules (MHCI) H2- Kb and H2-Db (KbDb-/-), which have enhanced cerebellar LTD at the parallel fiber-Purkinje cell synapses (pf-Pk LTD), can exhibit specific enhancements or deficits in oculomotor learning, depending on the recent history of experience. Our results indicate that a delicate balance between the enhanced plasticity rate versus an opposing, saturation effect determines the learning outcome. We hypothesized that the lower threshold for LTD in KbDb-/- mice allows spontaneous activity in the circuit to induce LTD, driving it towards saturation and reducing its availability to support new learning. Consistent with saturation, a biochemical marker of pf-Pk LTD indicated abnormally elevated levels of LTD in naive KbDb-/- mice, which exhibit a learning impairment. Moreover, optogenetic stimulation of cerebellar climbing fibers to induce pf-Pk LTD saturation in wild type mice created the same specific motor learning deficit as in KbDb-/- mice. In the KbDb-/- mice, behavioral pre-training designed to reverse the pf-Pk LTD saturation not only reversed the learning impairment, but also unmasked enhanced learning. Purkinje cell-specific rescue of MHCI H2-Db reversed both the impaired and the enhanced learning phenotypes in the KbDb-/- mice. Computational analysis identified synaptic properties that allow the same enhanced plasticity mechanism to yield either enhanced or impaired learning -- a strong saturation bias, and "stubborn", difficult to reverse states. Our results indicate that the recent history of activity in a circuit is critical in determining whether an enhanced plasticity rate or saturation dominates the capacity of a circuit for new learning.

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