Learning rules in cerebellar plasticity

• Timing-based learning rules and coincidence detection: Behavioral - Cerebellar motor conditioning Molecular - IP3 receptors Synaptic - Long-term depression at Purkinje neurons

• Spatial learning rules and spreading plasticity

• Tests and predictions

In eyeblink conditioning, tone must precede airpuff by >80 msec.

CALCIUM-DEPENDENT IP3 RECEPTOR DYNAMICS

Cerebellar Purkinje neuronDenk, Sugimori and Llinás (1995)Proc. Natl. Acad. Sci. 92:8279-8282

Denk, Sugimori, and Llinás (1995)

Wang, Denk and Hausser (2000), Nature Neuroscience 3:1266

Spine coincidence signals and LTD require calcium release

What causes the timing-dependence of coincidence detection?

• Time courses of glutamate, IP3, Ca2+

• Use-dependent facilitation

• IP3R activation/inactivation by Ca2+

• IP3R activation/inactivation by IP3

Conclusions (Part 1)

• Two-photon measurements reveal a form of coincidence detection in single dendritic spines based on calcium release

• The largest spine [Ca2+] elevations occur when presynaptic and postsynaptic activity are offset in time from each other

• Offset timing rules may arise from IP3/Ca2+ dynamics or IP3 receptor dynamics

• Parameters of cerebellar motor learning may correspond to the properties of IP3-dependent calcium release

Chemical two-photon uncaging

Wang, Khiroug and Augustine (2000)PNAS 97:8635

LTD induction causes a spreading decrease in receptor sensitivity

Furuta, Wang et al. (1999) PNAS 96:1193

Comparison of a new caging group,6-bromo-7-hydroxycoumarin-4-ylmethyl (Bhc),

with previous caged compounds

SCANNING TWO-PHOTON UNCAGING OF GLUTAMATE

Two-photon excitation: the third dimension of resolution

Chemical two-photon uncaging

• Achieving a multiphoton effect by chemical means

• A new design principle: multiple-site caging

• Reduction of effective spontaneous hydrolysis

• Effective cross-section is MUCH larger (109-fold) than true two-photon excitation

Wang and Augustine (1995)

Double-caged IP3

Goal: uncaging IP3 in single dendritic spines.S.E. Gelber, D. Sarkisov, J.W. Walker, S.S.-H. Wang

Collaborators Princeton University: Damon Clark, Mark Burish, Hao Yuan Kueh, Dmitry Sarkisov, Shy Shoham, and Jennifer Shultz

D.A. Clark, P.P. Mitra, and S.S.-H. Wang (2001): Nature, 411:189-193.

Bell Labs: Winfried Denk (Max Planck Institute), Partha Mitra, and David Tank University College London: Michael Häusser

S.S.-H. Wang, W. Denk, and M. Häusser (2000): Nature Neuroscience, 3:1266-1273.

Duke University: George Augustine, Diana Pettit (Einstein), and Leo Khiroug

S.S.-H. Wang, L. Khiroug, and G.J. Augustine (2000): Proc. Natl. Acad. Sci. USA, 97:8635-8640. D.L. Pettit, S.S.-H. Wang, K.R. Gee, and G.J. Augustine (1997): Neuron, 19:465-471.

S.S.-H. Wang and G.J. Augustine (1995): Neuron, 15:755-760. University of Wisconsin: Jeffery Walker, Shari Gelber (Columbia) University of California San Diego/Salk Institute: Roger Tsien, Toshiaki Furuta, Ed Callaway, Jami Dantzker-Milton, Timothy Dore, and Wendy Bybee T. Furuta, S.S.-H. Wang, J.L. Dantzker, T.M. Dore, W.J. Bybee, E.M. Callaway, W. Denk, and R.Y. Tsien

(1999): Proc. Natl. Acad. Sci. USA, 96:1193-1200.