Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_24_библиотеки_им_акад_М_И_Перельмана

Ca2+ signaling occurs in all cell types of the cerebellum and plays an essential role in cerebellar function. Ca2+ signaling can involve extracellular to intracellular Ca2+ signaling and/ or within cell Ca2+ signaling (Lamont and Weber 2012). A variety of cellular components participate in Ca2+ signaling (see Fig.45.1), although they can vary in type and level of expression across cerebellar cell types. Ca2+ signaling in the cerebellum has been extensively studied in Purkinje neurons, which express an abundance of Ca2+ signaling components, and in Bergman glia, which play an important regulatory role in the physiological function of Purkinje neurons. As the sole output neuron of the cerebellar cortex and an important inte­grator of cortical signals, Purkinje neurons play a central role in cerebellar functions such as motor coordination and, through connections with other brain regions, the processing of sensory, cognitive, and emotional information. Thus, the characteristics and role of Ca2+ signaling in Purkinje neurons are of particular interest, although Ca2+ signaling is a critical function of all cell types in the cerebellum (Cheron et al.

Ca2+ is widely but unequally distributed in the cerebellum and other brain regions. In particular, Ca2+ levels are consid­erably higher in the extracellular uid that baths the cells (~1–2mM) than in the cytosol of the cells (~100nM), a dif­ference that in neurons creates a driving force for Ca2+ inux. In addition, two organelles within the cytosol, the endoplas­mic reticulum and mitochondria, serve as Ca2+ storage ves­sels and have higher intra-organelle Ca2+ levels than cytosol Ca2+ level. There is also a driving force between these intra­cellular Ca2+ stores and cytosolic Ca2+. These pronounced concentration differences are a consequence of the imperme­ability of the cellular membranes to Ca2+ and other ions and the actions of various cell mechanisms (e.g., membrane ion channels, Ca2+ pumps) that regulate inux and efux of Ca2+ to or from the cytosol.

chapter on Synaptic Plasticity). Intracellular Ca2+ levels are a primary determinant of the directionality of synaptic plastic­ity (LTD or LTP). For example, at parallel ber to Purkinje neuron synapses, high intracellular Ca2+ levels favor LTD, while more moderate Ca2+ levels favor LTP (Rinaldo and Hansel 2010).

Intracellular Ca2+ is also critical for glial cell function, where it serves many of the same biochemical regulatory roles as in neurons. Astrocytes, which are the most abundant glial cell in the brain, have several mechanisms for Ca2+ sig­naling including Ca2+ inux through Ca2+ permeable mem­brane channels (e.g., some types of glutamate receptors) and Ca2+ release from intracellular stores (Lalo et al. 2011). Astrocytes are important regulators of neuronal and synaptic activity and Ca2+ plays a key role in these processes (Fiacco and McCarthy 2006; Verkhratsky 2006). For example, Bergman glia, a specialized type of astrocyte found only in the cerebellum, extend their processes around the excitatory dendritic synapses of Purkinje neurons creating microdo­mains in which glial/neuronal communication occurs. Bergman glia express many of the same neurotransmitter and neuromodulator receptors as Purkinje neurons, and two­way communication between Purkinje neurons and Bergman glia in the microdomains is basic to synaptic integration in the cerebellum. Synaptic activity (e.g., parallel ber activa­tion) and transmitters or other signaling molecules (e.g., glutamate, ATP, NO) released from axon terminals of neu­rons or glial processes in the microdomain interact with receptors on the Bergman glia resulting in an increase in intracellular Ca2+ levels, which are then propagated in waves to other Bergman glia through gap junctions of the glial net­work. The changes in intracellular Ca2+ produced by these waves can induce release of glial signaling molecules that inuence synaptic transmission at multiple synapses, alter astrocyte gene expression (e.g., expression of glutamate transporters, which remove glutamate from the synapse), alter biochemical state of the glia, and alter the structure and function of microdomains, all of which will affect Purkinje neuronal/Bergman glial communication and, consequently, information processing in the cerebellum (Müller and Kettenmann 1995; Metea and Newman 2006; Hoogland etal. 2009).

stimulation to be functionally active and enable Ca2+ ux. VGCCs are activated by changes in resting membrane potential, whereas ligand-gate channels are activated by neurochemicals such as neurotransmitters. In the unstimu­lated state, VGCCs and ligand gated channels are closed and impermeable to Ca2+. When activated, the channels open and Ca2+ inux occurs due to the large driving force for Ca2+ resulting from the prominent concentration differ­ence for Ca2+ between the outside (mM range) and inside (nM range) of the neuron. In the case of ligand-gated chan­nels, other ions may also ux through the channel in addi­tion to Ca2+ (e.g., Na+, K+).

The most prominent ligand-gated Ca2+ permeable chan­nels in the cerebellum are NMDA receptor (NMDAR) chan­nels and some subtypes of AMPA receptor channels, which when activated produce a membrane depolarization. These ligand-gated channels are activated by the neurotransmitter glutamate, although NMDA receptors also have a voltage requirement for activation. In addition to Ca2+, these chan­nels are permeable to Na+ and K+, a property that is relevant to the degree of depolarization that can be produced when the receptor is activated.

permeable to Ca2+, Na+, and K+ and when activated produce a membrane depolarization and Ca2+ inux.

Increases in intracellular Ca2+ levels during Ca2+ signaling are typically transient in nature. Ca2+ levels recover through a variety of mechanisms including Ca2+-binding proteins and membrane transport systems. A variety of cell proteins bind Ca2+ and act as Ca2+ buffers including calbindin, parvalbu­min, calmodulin, and calretinin, which differ in their Ca2+ buffering properties (Schwaller et al. 2002). These Ca2+­binding proteins play a central role in the regulation of cel­lular Ca2+ levels and vary in the level of expression across cell types, species, and age (Bastianelli 2003). Although most neurons express multiple types of Ca2+-binding pro­teins, certain cells types show more prominent expression of one or more Ca2+-binding proteins. For example, Purkinje neurons are noted for expression of calbindin and parvalbu­min, basket, stellate, and Golgi cells are noted for expression of parvalbumin, and granule neurons and unipolar bush cells are noted for expression of calretinin (Bastianelli 2003). All cerebellar neurons express calmodulin.