Backpropagating Action Potentials Enable Detection of Extrasynaptic Glutamate by NMDA Receptors

Yu-Wei Wu,Sergei Grebenyuk,Thomas J Mchugh,Dmitri A Rusakov,Alexey Semyanov

doi:10.1016/j.celrep.2012.03.007

Yu-Wei Wu, Sergei Grebenyuk + Show 3 more

Open Access

https://doi.org/10.1016/j.celrep.2012.03.007

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Abstract

SummarySynaptic NMDA receptors (NMDARs) are crucial for neural coding and plasticity. However, little is known about the adaptive function of extrasynaptic NMDARs occurring mainly on dendritic shafts. Here, we find that in CA1 pyramidal neurons, backpropagating action potentials (bAPs) recruit shaft NMDARs exposed to ambient glutamate. In contrast, spine NMDARs are “protected,” under baseline conditions, from such glutamate influences by perisynaptic transporters: we detect bAP-evoked Ca2+ entry through these receptors upon local synaptic or photolytic glutamate release. During theta-burst firing, NMDAR-dependent Ca2+ entry either downregulates or upregulates an h-channel conductance (Gh) of the cell depending on whether synaptic glutamate release is intact or blocked. Thus, the balance between activation of synaptic and extrasynaptic NMDARs can determine the sign of Gh plasticity. Gh plasticity in turn regulates dendritic input probed by local glutamate uncaging. These results uncover a metaplasticity mechanism potentially important for neural coding and memory formation.

Highlights

In many neurons, action potentials (APs) propagate into the axon and ‘‘backward’’ into the dendritic processes, where they contribute to synaptic plasticity (Magee and Johnston, 1997; Markram et al, 1997; Stuart and Hausser, 2001) and homeostatic changes in dendritic excitability (Campanac et al, 2008; Losonczy et al, 2008)
NMDA receptors (NMDARs) Contribute to backpropagating action potentials (bAPs)-Evoked Ca2+ Entry in Dendritic Shafts but Not in Spines We held a hippocampal CA1 pyramidal cell in whole-cell current-clamp mode, filled it with the Ca2+ indicator Fluo-4 (250 mM) and the morphological tracer Alexa Fluor 594 (20– 50 mM), and imaged Ca2+ transients induced by a single bAP in shafts and spines of the apical oblique dendrites (Figures 1A and 1B; AMPA, kainate, and GABAA receptors were blocked)
The amplitude of fluorescence Ca2+ responses (DG/R; Experimental Procedures) in the dendritic shafts was reversibly reduced to 89% ± 3% of baseline by the broad-spectrum NMDAR antagonist APV (50 mM) (n = 13, p = 0.001; Table 1; Figure 1C; Figure S1)

Summary

Introduction

Action potentials (APs) propagate into the axon and ‘‘backward’’ into the dendritic processes (backpropagating APs, bAPs), where they contribute to synaptic plasticity (Magee and Johnston, 1997; Markram et al, 1997; Stuart and Hausser, 2001) and homeostatic changes in dendritic excitability (Campanac et al, 2008; Losonczy et al, 2008). It has been shown that activation of synaptic NMDA receptors (NMDARs) by glutamate can be enhanced by bAPs that facilitate the removal of the NMDAR voltage-dependent Mg2+ block (Nevian and Sakmann, 2004; Schiller et al, 1998; Yuste and Denk, 1995). Whether and how dendritic NMDARs bound to ambient extracellular glutamate could be activated by bAPs is poorly understood. Experimental removal of the voltage-dependent Mg2+ block of NMDARs uncovers a tonic NMDAR-mediated current in hippocampal neurons (Cavelier and Attwell, 2005; Le Meur et al, 2007; Sah et al, 1989) even though the estimated level of ambient glutamate in quiescent hippocampal tissue is very low (Herman and Jahr, 2007). We asked whether bAPs can enable dendritic NMDARs in CA1 pyramidal cells to detect and respond to activity-dependent changes in the extracellular glutamate concentration

Results

Discussion

Conclusion