Opposing roles of synaptic and extrasynaptic NMDA receptors in neuronal calcium signalling and BDNF gene regulation

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Abstract

Neuronal responses to electrical activity-induced calcium signals are specified by the localization of the calcium entry site and the spatial properties of the calcium transient. Calcium flux through NMDA receptors located in the synapse initiates changes in synaptic efficacy and promotes pro-survival events, whereas calcium flux through extrasynaptic NMDA receptors is coupled to cell death pathways. The dialogue between the synaptic NMDA receptors and the nucleus is also modulated by extrasynaptic NMDA receptors, which shut down activity of CRE-binding protein (CREB) and antagonize the increase in brain-derived neurotrophic factor (BDNF) expression induced by synaptic NMDA receptors. The specification of the biological response by the localization of the receptor activated is a new concept in neuronal calcium signalling that can explain many of the opposing roles of NMDA receptors.

Introduction

Most electrical activity-dependent adaptations in the mammalian central nervous system are triggered by rapid, signal-induced changes in the intracellular concentration of calcium. The number of potential calcium-regulated biological responses is diverse, ranging from gene regulation, plasticity and learning, to survival and death 1., 2.. To achieve input–output specificity in their biological responses, neurons exploit the spatial and temporal diversity of activity-induced calcium signals [3]. For example, genomic responses are specified by the cellular compartment invaded by the calcium signal: calcium transients localized to the immediate vicinity of the site of calcium entry trigger the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathway 4., 5. and activate transcription mediated by the serum response element [4]; in contrast, increases in the nuclear calcium concentration induce a different genomic programme by activating gene expression mediated by CRE-binding protein (CREB) and/or CREB-binding protein (CBP) 6., 7..

Recently, another level of spatial calcium signalling has been suggested — namely, that the type of cellular response to stimuli causing calcium entry into neurons is determined by the localization of the particular calcium channel activated [8••]. The calcium entry channel in the centre of this study was the NMDA receptor, a glutamate- and voltage-gated channel that is permeable to calcium ions. NMDA receptors trigger long-term potentiation (LTP), can activate CREB/CBP-mediated gene expression, and promote pro-survival events 9., 10., 11.. Paradoxically, they are also capable of shutting down CREB function and initiating neuronal degeneration and/or death programs [11]. New results suggest that the former biological responses are induced by synaptic NMDA receptors, whereas the latter are a consequence of calcium entry through extrasynaptic NMDA receptors [8••]. Thus, NMDA receptor signalling may depend on the localization of the receptor activated; this provides a new conceptual basis for understanding the diverse (and in some cases even directly opposing) actions of NMDA receptors.

The implications of differential signalling by synaptic and extrasynaptic NMDA receptors for the aetiology and therapy of neurodegenerative conditions such as stroke have been reviewed recently [11]. Here we summarize the importance of synaptic and extrasynaptic NMDA receptors in regulating the early and late phases of neuronal plasticity associated with learning-related events; in particular, we focus on dendritic calcium signalling that regulates the surface expression of AMPA-type glutamate receptors, and on nuclear calcium signalling that controls transcription of the brain-derived neurotrophic factor (BDNF) gene (Figure 1).

Section snippets

Dynamic localization of NMDA receptors

NMDA receptors are found on the postsynaptic membrane at excitatory synapses. Through their carboxy-terminal tail they anchor to a multiprotein scaffold that forms a structure known as the ‘postsynaptic density’ 12., 13.. NMDA receptors are not, however, fixed at the synapse: a large fraction of synaptic NMDA receptors can move laterally to extrasynaptic sites [14••]. During periods of rapid synapse formation in cultures of hippocampal neurons, more than 65% of cell-surface NMDA receptors

Synaptic and extrasynaptic NMDA receptors in dendritic calcium signalling and plasticity

Synaptic NMDA receptors have a clearly defined role in plasticity. This process — the ability of neurons to change their synaptic efficacy according to previous experience — is traditionally divided into an early and a late phase. Calcium signals evoked by synaptic NMDA receptors control both phases: dendritic calcium signalling can, within minutes of NMDA receptor activation, alter synaptic connectivity, whereas on the timescale of hours nuclear calcium signalling contributes, through a

BDNF gene regulation: antagonistic control by synaptic and extrasynaptic NMDA receptors

Depending on the type of stimulation, increases in synaptic connectivity either revert to pre-stimulation levels within 2–4 h or are maintained for prolonged periods (in vivo LTP has been detected over several days). The maintenance or late phase of synaptic potentiation (and also synaptic depression [39]) depends on gene transcription taking place in a critical time window of about 2 h following induction [31]. Although it is still unclear exactly which of the numerous activity-regulated genes

Conclusions

NMDA receptor-induced calcium signals are a versatile carrier of information that can bring about plasticity, survival and death. The type of biological response is determined by the localization of the NMDA receptors activated. It will be important in the future to study NMDA receptor localization at the ultrastructural level and to determine the precise composition of synaptic and extrasynaptic NMDA receptor signalling complexes. A central aim is to develop specific inhibitors of

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

Acknowledgements

We thank Bill Wisden for discussion and comments on the manuscript.

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