Calcium (calx, Latin for lime) fulfils many regulatory, computational, and representational functions in the brain. Furthermore, it is instrumental in translating information across "levels and time domains in the brain (see below). In recent years much has been learned about the ways in which calcium ions (Ca2+) encode and modulate neuronal information, but the picture is far from being comprehensive.
In resting cells, intracellular Ca2+ is in the range of 10-100 nanomolar. Upon stimulation it could rise by several orders of magnitude. In many cases the information in the Ca2+ signal is encoded as spatiotemporal patterns of change rather than a tonic increase in concentration. Changes in cellular Ca2+ are due to influx from the extracellular milieu and release from intra-cellular stores. Both mechanisms generate elementary all-or-none Ca2+ signals, which are brief and localized (Bootman and Berridge 1995). Stimulus-induced combinations of intensity, timing, and location of these primitives of the 'Ca2+ language' generate a repertoire of Ca2+ codes (Bootman et al. 1997). The latter control cellular metabolism, structural dynamics, signal transduction, hormone release, differentiation, and growth (Berridge 1993; Petersen et al. 1994; Ghosh and Greenberg 1995; Matthews 1996). The introduction of novel technologies of molecular biology, cellular electrophysiology, and imaging has opened new vistas in the analysis of Ca2+ in neurons.
Especially noteworthy in the context of plasticity are the studies on the role of Ca2+ in mediating and modulating excitability and integrative properties in dendritic compartments (Markram et al. 1995; Magee et al. 1998); control of "neurotransmitter release (Matthews 1996; Goda and Sudhof 1997); modification of membrane "receptors (Barria et al. 1997); and modulation of gene expression (Bito et al. 1996; Dolmetsch et al. 1998).
The ubiquitousness of Ca2+ signalling in the nervous system makes it impractical to mention all its major functions in experience-dependent neuronal modification. These functions are performed at locations ranging from neuronal subcompartments to circuits, and on time-scales ranging from milliseconds to days and more. Ca2+ is required for elementary short-lived processes of "synaptic plasticity (Thomson 2001), and for the induction of "long-term potentiation, a popular cellular "model of longer-term neuronal plasticity (Nicoll and Malenka 1995). A few examples will serve to illustrate the role of Ca2+ in "acquisition, retention, and consolidation of learned behaviours. In the circuits that subserve "classical conditioning of defensive reflexes in "Aplysia,Ca2+ encodes information about the conditioned stimulus (CS). Furthermore, convergence of the CS and the unconditioned stimulus (US) takes place on a Ca2+/calmodulin-activated adenylyl cyclase ("coincidence detection; "intracellular signal transduc-tion cascade). The optimal activation of the enzyme requires that Ca2+ preceded the transmitter, hence mimicking the order dependency of CS-US presentation in classical conditioning (Yovell and Abrams 1992). Another Ca2+-regulated enzyme, the multifunctional Ca2+/calmodulin activated "protein kinase type II (CaMKII; Braun and Schulman 1995; De Koninck and Schulman 1998), was found to be essential in learning (Bach et al. 1995), "long-term potentiation (Barria et al. 1997), and neuronal development (Wu and Cline 1998). CaMKII is a major component of the postsynaptic density. It phosphorylates and modifies receptors, channels, and cytoskeletal elements. Experience-dependent autophosphorylation of the enzyme complex was proposed as a molecular storage mechanism immune to molecular turnover (Miller and Kennedy 1986). Another family of Ca2+ regulated protein kinase, PKC, was also implicated in learning (e.g. Scharenberg et al. 1991.) In addition, Ca2+ is involved in cellular consolidation: it regulates the activity of "CREB, and hence of the expression of cyclic adenosine monophosphate-response element (CRE)-regulated genes (Bito et al. 1996; "immediate early genes).
Why is it that Ca2+, rather than any other ion, plays such a key part in cellular activity in general and in plasticity in particular? Though in essence a teleological question with speculative answers, it does warrant consideration, because it could illuminate interesting properties of Ca2+ signalling systems. Possibly the physicochemical parameters of Ca2+, when considered in combination with those of critical Ca2+-binding sites in the cell, had from the early days of evolution fitted the demands of cellular function and plasticity better than those of other ions. The problem with this line of reasoning is that it is of the egg-and-the-hen type: was the cause the abundance of Ca2+, or the availability of the biological binding sites? This inherent issue notwithstanding, one appealing argument in favour of Ca2+ at the current stage of evolution is that the affinity of Ca2+ for important macromolecules in the cell is strong enough to allow rapid binding but not too strong to prevent rapid dissociation. This is important in cellular signalling in general and in fast plasticity in particular. For example, magnesium binds stronger to phospho-groups (Dawson et al. 1986); and monovalent ions are in general much worse in getting bound to biological macromolecules. The problem is highly complex, because, as mentioned above, it is not tonic Ca2+, but rather Ca2+ transients, which are most important in signalling. The life-span of these transients may not be sufficient for Ca2+ to equilibrate with binding sites in the cell (Markram et al. 1998b). Analysis of Ca2+ signalling, therefore, requires gigantic calculations of nonequilibrium Ca2+ dynamics. For our purpose suffice it to remember that the real-life role of Ca2+ in neuronal plasticity must be considered in the context of the simultaneous interaction of this ion with the network of the many Ca2+ binding molecules in the neuron.
It is also noteworthy that overall, the actions of Ca2+ in the neuron span orders of magnitude in time, space, and complexity (Bootman et al. 1997). This endows Ca2+ with a unique position to bridge molecular, cellular, and system levels of brain action (Dudai 1997b). The spatiotemporal pattern of Ca2+ is therefore a candidate parameter for future equations of the not-yet-available interlevel 'correspondence rules' in brain models and theories ("reduction).
Selected associations: Intracellular signal transduction cascade, Ion channel, Plasticity, Reduction, Stimulus
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