ReviewCa2+ signaling in dendritic spines
Introduction
Dendritic spines are tiny membranous compartments consisting of a head (volume ∼0.01–1μm3) connected to the parent dendrite by a thin (diameter ∼0.1μm) spine neck (reviewed in [1]). Spines are the receiving ends of most excitatory synapses in the brain. Each spine contains a postsynaptic density—a membrane-associated organelle comprising synaptic receptors, channels, signaling molecules and cytoskeletal proteins (reviewed in [2]). Some spines also have smooth endoplasmic reticulum (SER), while others are filled with polyribosomes [1]. Speculations regarding spine function have focused on the peculiar spine neck, which may serve to restrict diffusional exchange of signaling molecules between the spine head and parent dendrite 3., 4. or to impede synaptic currents [5]. Spines show activity- and experience-dependent morphological plasticity in vitro 6., 7. and in vivo [8], consistent with a role in memory storage in the mammalian brain [9].
Over the past ten years the development of confocal and two-photon microscopies [10], and the synthesis of fluorescent reporters of cellular function [11] have allowed a close look at the physiology of spines in intact neural tissues, focusing on Ca2+ dynamics (see also [12]). Spine Ca2+ has a crucial role in the induction of most forms of synaptic long-term potentiation (LTP) and long-term depression (LTD) [13]—the putative cellular mechanisms of learning and memory. Ca2+ regulates postsynaptic enzymes that trigger rapid modifications of synaptic strength and also activates transcription factors that facilitate long-term maintenance of these modifications [14]. A fundamental issue is how a single second messenger can encode all of these functions with any kind of specificity. The answer must lie, at least in part, in the details: signals comprising intracellular free calcium concentration ([Ca2+]) of different amplitude or time course, or in different locations may have different biochemical meanings for the cell.
Here we will review recent experiments related to [Ca2+] signaling in spines of pyramidal neurons and Purkinje cells in brain slices, while highlighting particularly pertinent experiments in other systems. As aspects of the morphological plasticity of dendritic spines have been reviewed recently 1., 15., 16., 17., we will not discuss them here.
Section snippets
Dendritic spines: electrical or diffusional compartments?
Direct measurements of diffusional transport through spine necks using fluorescence recovery after photobleaching (FRAP) have been used to probe compartmentalization by dendritic spines 18., 19••.. In these studies, a fluorophore was bleached in the spine head and the time for fluorescence recovery by diffusion from the parent dendrite was measured. The fluorescence recovery times were slow, up to a factor of 100 slower than expected for free diffusion. These measurements clearly show that
Sources of spine Ca2+
Ca2+ enters spines in response to synaptic excitation and postsynaptic electrical activity. The diffusional barrier provided by spine necks could function to keep [Ca2+] signals localized to spine heads and to concentrate Ca2+ in a small volume. An important factor shaping spine [Ca2+] transients is the dynamics of Ca2+ sources (Fig. 1).
Pyramidal neurons
Whereas synaptic activity produces synapse-specific [Ca2+] signals, back-propagating action potentials produce more global signals. In pyramidal neurons, action potentials radiate into the proximal dendrites (<200 μm from the soma), where they open voltage-sensitive Ca2+ channels (VSCCs) that admit Ca2+ into dendrites (reviewed in [27]) and spines [28]. [Ca2+] transients can be larger or smaller in spines than in their parent dendrites 29••., 30•.. Their fast rise time (<2ms) in spines shows
Purkinje cells
In contrast to the situation in pyramidal neurons, in cerebellar Purkinje cells the contribution of Ca2+ stores to synaptic [Ca2+] and its role in the induction of synaptic plasticity are beginning to be understood. Purkinje cells lack NMDARs but their dendrites and spines are filled with an intricate ER that is studded with inositol 1,4,5–triphosphate (IP3) receptors, suggesting that there is a connection between PF activation, activation of metabotropic glutamate receptors (mGluRs), and IP3
Regulation of spine [Ca2+]
In addition to the dynamics of Ca2+ sources, spine [Ca2+] signals are shaped by endogenous Ca2+ buffers, the properties of Ca2+ extrusion mechanisms, and transport of Ca2+ between dendrite and spine (Fig. 1). To explore these mechanisms, it is advantageous to use back-propagating action potentials as stimuli. Action potentials open VSCCs for sufficiently brief periods (<1ms) to be considered instantaneous sources of Ca2+ [51], simplifying the interpretation of the resulting [Ca2+] dynamics 28.,
Spine [Ca2+] and synaptic plasticity
A postsynaptic [Ca2+] rise is required to induce LTP and LTD in cortex (reviewed in [13]). During tetanic stimuli, such as those required to produce LTP, spine Ca2+ reaches concentrations greater than 10μM [34], whereas the stimuli required to induce LTD produce smaller and longer accumulations of Ca2+ 28., 36••., 37•., 38.. Recently, a number of studies have used pairing of action potentials and synaptic stimuli to induce synaptic plasticity ([53]; reviewed in [54]). These induction paradigms
Using spine [Ca2+] to study Ca2+ sources
Although most interest in spine [Ca2+] dynamics stems from the role of Ca2+ in synaptic plasticity, observations of [Ca2+] transients have also been used to uncover the properties of Ca2+-permeable channels, such as NMDARs and VSCCs, in their native environments. Because of the diffusional isolation of the spine head from the dendrite, Ca2+ accumulations in the spine depend only on Ca2+ entering through sources located on the spine membrane. Hence, if a class of Ca2+-permeable channels can be
Conclusions
Dendritic spines are biochemical microcompartments that are isolated from their parent dendrites and neighboring spines. Spines compartmentalize Ca2+ and perhaps other messengers, such as IP3 and Na+ [59]. Imaging studies of spine [Ca2+] dynamics have revealed that Ca2+ can enter spines through voltage-sensitive and ligand-activated channels, as well as through Ca2+ release from intracellular stores. In Purkinje neurons, the relationships between spine [Ca2+] signals and the induction of
Acknowledgements
We thank Mike Hausser, Thomas Oertner, Thomas Pologruto and Esther Nimchinsky for comments on the manuscript.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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