ReviewThe role of calcium in synaptic plasticity and motor learning in the cerebellar cortex
Highlights
► Calcium contributes to most forms of synaptic plasticity in the cerebellar cortex. ► Calcium-dependent plasticity may influence motor coordination and learning. ► Many mutant mouse models with altered calcium signaling exhibit motor dysfunction.
Introduction
The cerebellum, which is Latin for “little brain”, lies posterior to the pons and medulla oblongata and inferior to the occipital lobes of the cerebral hemispheres. Cerebellar damage often leads to symptoms such as ataxia, asynergy, dysmetria, and motor learning deficits in humans (Schmahmann, 2004, Stoodley and Schmahmann, 2010) as well as in animals (Lalonde and Strazielle, 2001, Rinaldo and Hansel, 2010). Therefore, the ability to modulate motor commands and fine-tune complex movements has largely been attributed to the cerebellum. Recent evidence suggests that the cerebellum may have cognitive functions and play a role in the processing of emotions (Strick et al., 2009). In addition, the cerebellum has received considerable attention because of its proposed role in motor learning behavior (Ito, 2006). Central to motor learning theories are Purkinje cells (PCs) of the cerebellar cortex. PCs are important because they represent the only output cell of the cerebellar cortex and as such, play a vital role in normal cerebellar function, i.e. motor coordination. In addition to motor coordination, PCs are postulated to play a major role in certain forms of motor learning, including associative eyeblink conditioning and adaptation of the vestibulo-ocular reflex (Schmolesky et al., 2002). Synaptic plasticity in PCs has long been postulated to represent the underlying cellular changes that lead to motor memories. Long term depression (LTD) at parallel fiber (PF)-PC synapses in particular remains a widely accepted vertebrate model for the cellular mechanism that underlies synaptic changes during motor learning and memories in the cerebellum, and several molecular components have been identified which appear to be necessary for its induction, including glutamate receptors and various kinases (Massey and Bashir, 2007). It was long thought that PF-PC synapses were the only synapses capable of plasticity in the cerebellar cortex, however in recent years plasticity has been described at several other synapses in the cortex (Hansel et al., 2001, Dean et al., 2010). In this review, we provide a brief overview of the types of synaptic plasticity present in the cerebellar cortex, with a particular emphasis on the role of calcium in those synaptic changes.
Section snippets
Basic circuit in the cerebellar cortex
The cell bodies of PCs are found in a specific layer of the cerebellar cortex appropriately named, the PC layer. The dendrites of PCs project into the molecular layer of the cortex, while the axons of PCs pass through the granule cell (GC) layer and project out of the cerebellar cortex (see Fig. 1). PCs receive two types of excitatory synaptic inputs. The first is from climbing fibers (CFs), which arise from the inferior olive (IO) of the brain stem and carry sensory, and perhaps motor
The role of calcium in cell signaling
The calcium ion (Ca2+) is arguably one of the most important, if not the most important ion in the nervous system, because of the wide variety of activities in which it is reported to be involved. For example, Ca2+ is intricately involved in the growth and development of neurons (Ghosh and Greenberg, 1995, Spitzer and Ribera, 1998, Takei et al., 1998) and it is a necessary component for normal neurotransmission in the brain (Berridge, 1998, Iwasaki et al., 2000), spinal cord (Bertrand et al.,
Purkinje cells
Activation of groups of PFs in vitro causes the release of glutamate into the synaptic cleft, which results in brief excitatory postsynaptic potentials (EPSPs; Eilers et al., 1995). If the stimulation intensity is high enough, the result is the generation of action potentials in PCs termed simple spikes, which can occur at various frequencies in vivo depending on various vestibular and motor signals (Barmack and Yakhnitsa, 2003, Dean et al., 2010). Activation, and release of glutamate from CFs,
Insights from transgenic mouse models
Immense strides have been made to advance techniques used to research calcium's involvement with cerebellar plasticity and motor learning. One of the most useful techniques is the utilization of genetic knockout mice or other mutant mice, as it allows for this phenomenon to be studied in more detail in vivo. Many varieties of mutant mice are available for studies of cerebellar plasticity and signaling, such as the hotfoot mouse (Draski et al., 1994, Mandolesi et al., 2009). The hotfoot mouse
Summary and concluding remarks
The cerebellum has long been accepted as a part of the brain involved with fine motor coordination and learning. As described, there are many components to the circuit in the cerebellar cortex. Original motor learning theories suggested that learning took place solely at the synapses between PFs and PCs, and that most, if not all other synapses in the cerebellar cortex were not plastic. Clearly, this view was overly simplistic, as plasticity has now been described at several synapses in the
Acknowledgments
The authors would like to acknowledge current research funding support from the Natural Sciences and Engineering Research Council (NSERC) and the Canada Foundation for Innovation.
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