Research Summary

Cellular mechanisms of plasticity in the cerebellum.

Research Statement

In Marr-Albus-Ito models of cerebellar function, coactivation of the climbing fiber (CF) synapse, which provides massive, invariant excitation of Purkinje neurons (coding the unconditioned stimulus), together with a graded parallel fiber synaptic array (coding the conditioned stimulus) leads to long-term depression (LTD) of parallel fiber (PF)-Purkinje cell (PC) synapses, underlying production of a conditioned response. PF-LTD is generally assumed to provide the cellular basis for several forms of cerebellar motor learning.

In my lab, we examine cellular mechanisms underlying long-term potentiation (LTP) and LTD at PF-PC synapses as well as LTD at CF-PC synapses.

We have recently shown that bidirectional plasticity at PF synapses is governed by induction rules that operate inverse to their counterparts at e.g. hippocampal synapses:

• PF-LTD needs a larger calcium transient for its induction than LTP and
• PF-LTD is kinase-dependent, whereas PF-LTP is phosphatase-dependent.

Another unique feature of cerebellar plasticity is that LTP and LTD at PF synapses are under control of the heterosynaptic CF input. Moreover, previous CF-LTD induction reduces the probability of subsequent PF-LTD induction. A new line of research focuses on activity-dependent changes in the intrinsic excitability of Purkinje cells. Moreover, we try to characterize how clinically relevant substances, which negatively (alcohol) or positively (memory-enhancers, such as ampakines) interfere with AMPA receptor-mediated transmission, affect cerebellar plasticity and learning. Experimentally, we use whole-cell patch-clamp recordings from PCs in rat or mouse cerebellar slices. In some experiments, we combine the electrophysiological recordings with microfluorometric imaging techniques using a cooled CCD camera.

Recent publications

Hansel, C., and Linden, D.J. (2000). Long-term depression of the cerebellar climbing fiber-Purkinje neuron synapse. Neuron 26, 473-482. (Pubmed)

Hansel, C., Linden, D.J., and D’Angelo, E. (2001). Beyond parallel fiber LTD: the diversity of synaptic and non-synaptic plasticity in the cerebellum. Nature Neurosci. 4, 467-475. (Pubmed)

Shen, Y., Hansel, C., and Linden, D.J. (2002). Glutamate release monitored during LTD at the cerebellar climbing fiber-Purkinje neuron synapse. Nature Neurosci. 5, 725-726. (Pubmed)

Weber, J.T., De Zeeuw, C.I., Linden, D.J. and Hansel, C. (2003). Long-term depression of climbing fiber-evoked calcium transients in Purkinje cell dendrites. Proc. Natl. Acad. Sci. USA 100, 2878-2883. (Pubmed)

Coesmans, M., Weber, J.T., De Zeeuw, C.I. and Hansel, C. (2004). Bidirectional parallel fiber plasticity in the cerebellum under climbing fiber control. Neuron 44, 691-700. (Pubmed)

Belmeguenai, A., and Hansel, C. (2005). A role for protein phosphatases 1, 2A, and 2B in cerebellar long-term potentiation. J. Neurosci. 25, 10768-10772. (Pubmed)

Hansel, C. (2005). When the B-team runs plasticity: GluR2 receptor trafficking in cerebellar long-term potentiation. Proc. Natl. Acad. Sci. USA 102, 18245-18246.(Pubmed)

De Ruiter, M.M., De Zeeuw, C.I., and Hansel, C. (2006). Voltage-gated sodium channels in cerebellar Purkinje cells of mormyrid fish. J. Neurophysiol. 96, 378-390. (Pubmed)

Van Beugen, B.J., Nagaraja, R.Y., and Hansel, C. (2006). Climbing fiber-evoked endocannabinoid signaling heterosynaptically suppresses presynaptic cerebellar long-term potentiation. J. Neurosci. 26, 8289-8294. (Pubmed)

Hansel, C., de Jeu, M., Belmeguenai, A., Houtman, S., Buitendijk, G., Andreev, D., De Zeeuw, C.I., and Elgersma, Y.: CaMKII is essential for cerebellar LTD and motor learning. Neuron. 2006 51(6):835-43. (Pubmed)

Han V., Zhang Y., Bell C., Hansel C.:  Synaptic plasticity and calcium signaling in purkinje cells of the central cerebellar lobes of mormyrid fish: J. Neurosci., 27 (49):  13499-13512, 2007.

Jorntell H., Hansel C.:  Synaptic memories upside down:  bidirectional plasticity at cerebellar parallel fiber-purkinje cell synapses:  Neuron 52:  227-238, 2006.

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