Keywords

1 Parallel Fiber LTD

A persistent attenuation of parallel fiber-Purkinje cell synapse is produced when parallel fiber and climbing fiber inputs to a Purkinje cell are stimulated together at low frequency (Ito et al. 1982). The parallel fiber LTD is associative and saturable upon repeated parallel fiber stimulation. Strong parallel fiber stimulation or conjunctive climbing fiber/parallel fiber stimulation induces parallel fiber LTD through the activation of postsynaptic metabotropic glutamate receptors (mGluR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), and subsequent rise of internal Ca2+. The activation of protein kinase Cα (PKCα) and α-Ca2+/calmodulin-dependent protein kinase II (αCaMKII) are required. The cytosolic phospholipase A2α (cPLA2α)/cyclooxygenase-2 cascade plays important roles in this LTD by acting on upstream PKCα. Cannabinoid receptor 1 (CB1R) and nitric oxide/soluble guanylyl cyclase/cGMP-dependent protein kinase/phosphatase pathways are also invovled (Bear and Linden 2000; Safo and Regehr 2005). Parallel fiber LTD is expressed postsynaptically, as a reduction in the number of surface AMPARs produced by clathrin-dependent endocytosis (Wang and Linden 2000).

2 Parallel Fiber LTP

Parallel fiber-Purkinje cell synapses undergo two forms of homosynaptic LTP, depending on stimulus frequency. Four to 8 Hz parallel fiber stimulation induces presynaptically-expressed LTP, which is associated with a decrease in paired-pulse facilitation (Salin et al. 1996) and evoked glutamate transport currents in glial cells (Linden 1998). Furthermore, 4–8 Hz LTP is mediated by the presynaptic adenylyl cyclase/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway (Hansel et al. 2001). Evidence from cerebellar cultures shows that 4-Hz LTP is mediated by PKA-mediated phosphorylation of the active zone protein RIM1α (Lonart et al. 2003).

In contrast, 1-Hz parallel fiber stimulation induces a postsynaptically-expressed LTP. This LTP requires a low level of Ca2+ in Purkinje cells (Coesmans et al. 2004), which leads to the activation of cPLA2α, the liberation of arachidonic acid, and the production of 2-arachidonoylglycerol (2-AG). Activated CB1R on presynaptic terminals by 2-AG triggers the activation of nitric oxide synthase and produces a low-level release of nitric oxide from parallel fiber terminals (Wang et al. 2014). Afterwards, nitric oxide works postsynaptically with serine/threonine phosphatases to promote the required trafficking of AMPARs. Since 1-Hz LTP and parallel fiber LTD are both expressed postsynaptically, it is suggested that 1-Hz LTP is a resetting mechanism for motor learning and causes the extinction of learned associations.

3 Climbing Fiber LTD

5 Hz tetanization of climbing fibers evokes a LTD at climbing fiber-Purkinje cell synapse, which is homosynaptic and saturable (Hansel and Linden 2000). Climbing fiber LTD requires intracellular Ca2+ and the activation of mGluR1 and PKC, and is expressed postsynaptically (Shen et al. 2002). Climbing fiber LTD is hypothesized to control the integrative response of Purkinje cell because complex spikes are attenuated after 5 Hz tetanization. Interestingly, 5 Hz tetanization at climbing fibers also induces a LTP of glutamate transporter EAAT4 (Shen and Linden 2005).

4 Interneuron-Purkinje Cell Synaptic LTP

LTP of GABAA receptor-mediated inhibitory postsynaptic currents in Purkinje cells is induced by repetitive climbing fiber activation (Kano et al. 1992). This inhibitory LTP requires a postsynaptic Ca2+ transient from internal Ca2+ stores and the activation of CaMKII and PKA. An early study showed that simultaneous activity of inhibitory synapses is needed for the induction of inhibitory LTP (Kano 1996), but another study showed that simultaneous inhibitory activity suppresses the inhibitory LTP (Kawaguchi and Hirano 2000). Interneuron-Purkinje cell synaptic LTP has a major influence on Purkinje cells throughput, as it modulates the spike firing pattern in Purkinje cells (Häusser and Clark 1997).

5 Plasticity of Mossy Fiber-Granule Cell Synapses

Mossy fiber-granule cell synapses provide a large potential substrate for information storage. Activation of mossy fibers combined with postsynaptic depolarization of granule cells results in mossy fiber LTP (D’Angelo et al. 1999), which requires postsynaptic depolarization, Ca2+ influx and activation of NMDA receptors, mGluR, and PKC. The inhibitory input by Golgi cells also affects the expression of mossy fiber LTP. In contrast, protracted low-frequency stimulation causes mossy fiber LTD (Gall et al. 2005). Mossy fiber LTP and LTD promote the population (summated) and sparse (local) coding, respectively, in the granular layer.

6 Plasticity in the Deep Cerebellar Nuclei (DCN)

Mossy fiber-DCN plasticity depends on the excitation of DCN cells (Pugh and Raman 2006) while Purkinje cell-DCN plasticity depends on the excitation of both DCN cells and Purkinje cells (Aizenman et al. 1998). DCN cells can also generate a plasticity of intrinsic excitability. Mossy fiber-DCN plasticity and intrinsic excitability can work together to generate a coincidence detector driven by intracellular calcium transients.

7 Plasticity of Intrinsic Excitability in Purkinje Cells

Purkinje cell excitability can be enhanced by somatic current injections or parallel fiber stimulation. Signal cascades for LTP of intrinsic excitability include local Ca2+ in spines and protein phosphatases. The interactions between these molecules and PKA and casein kinase 2 result in a downregulation of small conductance Ca2+-activated potassium channels, thereby reducing an intrinsic inhibitory influence. LTP of intrinsic plasticity occludes subsequent parallel fiber LTP, but facilitates parallel fiber LTD (Coesmans et al. 2004). LTP of intrinsic plasticity can be locally restricted to one synapse, but can also affect a large number of synapses, depending on the identity and location of intrinsic conductances altered.

8 Spike-Timing Dependent Plasticity (STDP) in Cerebellum

Since the first report by Ekerot and Kano (1989), a series of studies have determined that parallel LTD is induced best when parallel fiber stimulation precedes climbing fiber-evoked complex spikes in Purkinje cells by 50–250 ms, suggesting an anti-Hebbian STDP mechanism in the cerebellum. Cerebellar STDP differs from that at hippocampal synapses, in that it is independent of axonal spike output. Rather, external climbing fiber stimulation and locally elicited Ca2+ spikes play a key role.

9 Conclusions

It is clear now that cerebellar learning is an integrated process involving numerous forms of synaptic plasticity in the cerebellar cortex and nuclei, where various specific spatial patterns are organized. Channeling begins from granular layer and is concluded in the molecular layer, where Purkinje cells integrate signals from different inputs. Plasticity is also organized in specific temporal patterns in the granular and molecular layer. In this view, the mechanisms for cerebellar learning should be viewed as the integration of various plasticities in the cerebellar cortex and nuclei (Fig. 43.1).

Fig. 43.1
figure 1

A summary of plasticity in the cerebellar circuit (Modified with permission from Hansel et al. 2001). The occurrence of long-term plasticity is coded with color: red indicating potentiation and blue indicating depression. The intrinsic excitability is labeled with action potentials in somata, whereas conventional synaptic LTP or LTD is labeled with bars of colors at synapses

Full size image