Thus, this disynaptic plasticity in the feedforward inhibition onto PCs provides a possible answer to the emerging question of what the role of the climbing fibers might be when climbing-fiber-induced PF-PC LTD is not essential. Similarly, PCs also display intrinsic plasticity (Belmeguenai et al., 2010), and protein kinases may well be required for

persistent use-dependent modulation of one or more of the ion channels involved. Finally, the kinases might also play a role in presynaptic plasticity at the PC to cerebellar nuclei neuron synapse (Pedroarena and Schwarz, 2003) and/or postsynaptic plasticity at the mossy fiber or climbing fiber collateral to cerebellar nuclei neuron synapse (Pugh and Raman, 2008 and Zhang SRT1720 mw and Linden, 2006). Thus, combined deficits in plasticity at the PF to PC synapse, the molecular layer interneuron to PC synapse, the PC to cerebellar nuclei neuron synapse, and the collateral to cerebellar nuclei neuron synapse, and in the intrinsic plasticity of PCs, provide interesting alternative explanations for the behavioral

phenotypes observed in the PC-specific PKC, PKG, and αCamKII mutants (De Zeeuw et al., 1998, Feil et al., 2003 and Hansel et al., BIBW2992 2006). The mutations in the PICK1 KO, GluR2Δ7 KI, and GluR2K882A KI mutants were global, i.e., not cell specific. Thus, it was remarkable that both cerebellar motor performance and motor learning were normal, despite the fact that the mutations affect multiple cell types in both the cerebellum and its supportive systems. The global character of the mutations even further strengthens the implications of the general absence of a necessary and sufficient correlation between our cell physiological and behavioral findings. One would expect more deficits in general, and it raises the possibility that the affected protein and receptors, as well as the correlated cell physiological deficit in LTD, can be readily compensated for in general. The same argument may hold for the specific concept Idoxuridine that was put forward by

the Marr-Albus-Ito hypothesis, i.e., the idea that climbing fiber activity during motor learning weakens the PF influence onto PCs and thereby reduces their output. As explained above, there may be different climbing-fiber-driven mechanisms in place that can act simultaneously under normal conditions and that can compensate for each other’s absence in particular mutant mice. For example, the climbing fibers might be able to both depress the PF to PC synapse and potentiate the molecular layer interneuron to PC synapse (Jörntell et al., 2010), and both could ultimately lead to a depression of PCs’ simple spike activity. Thus, in principle a climbing-fiber-driven reduction in simple spikes may still occur during learning in the PICK1 KO, GluR2Δ7 KI, and GluR2K882A KI mutants, despite a blockade of LTD at the PF to PC synapse.