The role of the endoplasmic reticulum Ca2+ store in the plasticity of central neurons

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The smooth endoplasmic reticulum (SER) is a well-characterized buffer and source of Ca2+ in both axonal and dendritic compartments of neurons. Ca2+ release from the SER can be evoked by stimulation of the ryanodine receptor or the inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] receptor. Both receptors can couple to the activation of neurotransmitter-gated receptors and voltage-gated Ca2+ channels on the plasma membrane, thus enabling the SER to discriminate between different types of neuronal activity. In axonal terminals, Ca2+-induced Ca2+ release (CICR) mediates spontaneous, evoked and facilitated neurotransmission. Store release might also regulate the mobilization and recycling of synaptic vesicles. In the dendritic compartment, the distribution of Ins(1,4,5)P3 receptors and ryanodine receptors influences the intracellular encoding of neuronal activity. Thus, the functionality of the Ca2+ store can affect both the polarity and the spatial extent of Ca2+-dependent shifts in synaptic efficacy. In hippocampal neurons, for example, CICR in the spine heads underlies homosynaptic plasticity, whereas heterosynaptic plasticity is mediated by Ins(1,4,5)P3-dependent Ca2+ signalling. Purkinje neurons primarily express Ins(1,4,5)P3 receptors in the spine heads, and long-term depression of synaptic efficacy is crucially dependent on Ins(1,4,5)P3.

Introduction

Synaptic plasticity within hippocampal and cerebellar networks is the probable neural substrate for spatial and motor learning, respectively. Many forms of synaptic plasticity exist; these vary in locus, mechanism and duration of expression but they all depend on Ca2+ as a necessary inductive trigger. In this article, the role of intracellular Ca2+ stores in modulating transmission at hippocampal and cerebellar synapses will be discussed. Ca2+ influx into presynaptic and postsynaptic compartments can be mediated by voltage-gated or neurotransmitter-gated Ca2+ channels in the plasma membrane. Ca2+ influx is driven by a 1000-fold concentration gradient between the extracellular and intracellular spaces {cytosolic [Ca2+] is ∼100 nM}. Ca2+ signals are restricted spatially and temporally by high-capacity Ca2+-binding proteins in the cytosol and transmembrane Ca2+ pumps on the plasma membrane and intracellular organelles. The best characterized of the Ca2+ signalling organelles is the smooth endoplasmic reticulum (SER), a heterogeneous endomembrane system that extends from the neuronal soma to most cell compartments, including axons and dendritic spines [1]. Ca2+ is sequestered into the SER lumen by high-affinity (Km∼1 μM) sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pumps, which can be inhibited by pharmacological agents such as thapsigargin and cyclopiazonic acid (CPA). Depletion of Ca2+ stores also generates Ca2+ influx via store-operated channels in both axons and dendrites 2, 3, 4. During Ca2+ uptake into the SER, the luminal free [Ca2+] can reach 500 μM, whereas the bound [Ca2+] can be up to three orders of magnitude higher [1]. Even at rest, luminal [Ca2+] can be four times higher than in the cytosol and thus the SER can provide a ready source of Ca2+. The rapid release of Ca2+ from the SER is evoked by stimulation of two largely homologous receptor types on the SER, which are named for their affinity for either the plant alkaloid ryanodine or the cell metabolite inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3].

Section snippets

Receptor pharmacology

Ryanodine receptors have multiple allosteric Ca2+-binding sites responsible for triggering Ca2+-induced Ca2+ release (CICR) from the SER following rises in cytosolic [Ca2+]. In rodent cerebellar tissue, these receptors are maximally responsive to cytosolic [Ca2+] in the 1–10 μM range, and are inhibited by cytosolic [Ca2+] in the low millimolar range [5]. Ins(1,4,5)P3 is a metabolic product of phospholipase C (PLC) activity, which at excitatory synapses is linked to the stimulation of

Receptor localization

Immunohistological techniques have revealed heterogeneous patterns of ryanodine receptor and Ins(1,4,5)P3 receptor expression between and within neuronal cell types. The ryanodine receptor family has three isoforms typically associated with skeletal muscle (RY1), cardiac muscle (RY2) and brain (RY3). However, the RY2 receptor is also present at high density in many neuronal somata, and the RY1 receptor is detected in the cerebellum and, to a lesser extent, in the hippocampus 10, 11. The

Evoked neurotransmitter release and facilitation

Exocytosis of synaptic vesicles at hippocampal synapses can be evoked within 150 μs of a presynaptic action potential (AP) [15], and is dependent on the influx of Ca2+ through voltage-gated Ca2+ channels (VGCCs), which produce a high [Ca2+] at the release site (Figure 1). It is unclear which VGCC subtypes are involved and to what extent CICR contributes to neurotransmitter release. The AP-evoked Ca2+ transient in presynaptic boutons of hippocampal CA3 neurons is depressed by bath application of

Collateral fibre–CA synapses and NMDA receptor-dependent pathways

Long-term potentiation (LTP) at CA3–CA3 and CA3–CA1 collateral synapses in hippocampal slices is induced by asynchronous presynaptic and postsynaptic activity, whereas long-term depression (LTD) is induced by out-of-phase activity [35]. A key feature of both LTP and LTD at collateral synapses is that their induction is blocked by the n-methyl-d-aspartate (NMDA) receptor antagonist d-2-amino-5-phosphonovalerate (APV) [35]. Imaging of individual spines of CA hippocampal neurons has shown that

Neuronal excitability

The excitability of the plasma membrane can be modulated by Ca2+-dependent changes in K+ conductances. These conductances underlie the afterhyperpolarizing potentials (AHPs) that follow bursts of spikes and limit their frequency of neuronal output, and might enhance the temporal precision of EPSP–AP pairings. The early components of the AHP are mediated by big-conductance (BK) and small-conductance (SK) K+ channels [73]. Although SK channel activity is modulated by input to mGlu receptors, the

Concluding remarks

The SER is a dynamic Ca2+ store that is closely coupled to neuronal activity in both presynaptic and postsynaptic neuronal compartments. Although the way in which the SER achieves its diversity of function is not clear, it appears to be essential to the varied behaviour of different synapses. For example, the coupling of the SER to particular VGCC subtypes might determine the contribution of CICR to neurotransmitter release. Similarly, the architecture of the SER at vesicle-release sites might

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