Review
NMDA receptor-mediated dendritic spikes and coincident signal amplification

https://doi.org/10.1016/S0959-4388(00)00217-8Get rights and content

Abstract

Dendrites of cortical neurons possess active conductances, which contribute to the nonlinear processing of synaptic information. Recently it has been shown that basal dendrites can generate highly localized spikes mediated by NMDA receptor channels. These spikes may serve as a powerful mechanism to detect and amplify synchronously activated spatially clustered excitatory synaptic inputs in individual dendritic segments, and may enable parallel processing in several integrative dendritic subunits.

Introduction

The way in which single neurons process incoming synaptic information has significant consequences for network function. Most neurons have dozens of dendritic branches, each with hundreds of synapses. With the introduction of new techniques to visualize and record directly from dendrites, it has become clear that dendrites possess many different active conductances, including Na+, Ca2+, K+ and N-methyl d-aspartate (NMDA) receptor (NMDAR) channels (for reviews see 1., 2., 3., 4.). These channels, when activated, change the biophysical properties of dendrites and endow them with rich nonlinear computational capabilities. Active conductances support the back-propagation of action potentials into the dendritic tree [5], cause focal rises in Ca2+ in dendrites [6], and shape or boost synaptic potentials 7., 8., 9., 10., 11., 12..

Nonlinearity, such as amplification and attenuation, lies at the heart of neural network computation. Supralinear amplification is a phenomenon in which the voltage end product of concomitantly activated synaptic potentials is greater than their arithmetic sum. The most prominent dendritic mechanism for supralinear amplification of synaptic potentials is the initiation of local dendritic spikes. Several types of dendritic spikes have been described, including sodium, calcium and the recently described NMDAR-channel-mediated spikes (reviewed in [4]). NMDAR channels have important direct electrical effects, which fall along a continuum ranging from graded boosting of excitatory postsynaptic potentials (EPSPs), which support the initiation of spikes mediated mainly by other active conductances, to full-blown NMDA-dominated spikes. In this review, we focus mainly on the distinct role of NMDAR channels in supralinear dendritic amplification.

Section snippets

Active properties of NMDAR channels

The ligand gated NMDAR channels are voltage sensitive. Glutamate-bound NMDAR channels have an N-shaped current–voltage curve, with a region of ‘negative slope’ conductance caused by relief of Mg2+ block [13], which can be ‘added’ on to similar curves resulting from other depolarization-activated conductances. Fig. 1 shows the effect of increasing NMDAR conductance in the membrane of a compartment. There are three qualitatively different regimes: ‘boosting’, ‘bistable’ and ‘self-triggering’.

A

Graded NMDAR boosting of EPSPs

NMDAR channels have been shown to boost synaptic potentials. When pairs or trains of EPSPs are administered, NMDAR channels amplify the later EPSPs 14., 15., 16., 17., 18.. Moreover, this phenomenon has been described for heterosynaptic activation as well [18]. Recently, Cash and Yuste [19•] directly addressed the question of spatial summation of EPSPs in dendrites of hippocampal pyramidal neurons. Coincident AMPA-receptor-mediated EPSPs into the same dendrite generally sum sublinearly, because

Local dendritic spikes

The dendritic tree of pyramidal neurons is composed of apical and basal arborizations. Most synaptic inputs terminate on thin apical and basal dendritic branches [20]. The available experimental data regarding dendritic spikes have been obtained mainly from the thick apical dendrites, that is, the apical trunk and main tuft branches. In these dendritic branches, two types of local dendritic spikes have been described: Na+-dominated fast spikes 21., 22., 23., 24., 25., and Ca2+-dominated spikes

NMDA-assisted apical dendritic Ca2+ spikes

Initiating apical dendritic Ca2+ spikes is facilitated by the activation of NMDAR channels. Blockade of NMDAR channels eliminates synaptically evoked dendritic Ca2+ spikes in the apical dendrites of both layer-5 neocortical and basolateral amygdala pyramidal neurons 28., 33•.. In this case the axonal initiation zone can no longer be driven by the distal apical initiation zone (Fig. 2). Re-initiation cannot be achieved by increasing the amplitude or duration of isolated AMPA-mediated EPSPs, or

NMDAR-dominated spikes in basal dendrites

As mentioned above, we and our co-workers [32••] recently described a new ionic mechanism for initiating local dendritic spikes in the thin dendrites of the basal tree— spikes mediated predominantly by NMDAR channels (Fig. 3). NMDA spikes have been demonstrated in thin basal dendrites in neocortical and CA1 hippocampal pyramidal neurons (32••., 34.; and JS, unpublished data). Na+ and Ca2+ voltage-gated channels are important in triggering NMDA spikes—they lower the activation threshold and the

Functional role of dendritic NMDA spikes

The ionic mechanism underlying NMDA spikes endows them with unique features, which have several important physiological implications.

First, localization of the spike to the input dendrite. The fact that NMDAR channels mediate spikes both ensures that these spikes will remain restricted to the active synapses, and potentially enables parallel processing in different branches of the basal tree. In contrast, local Ca2+ spikes recorded in the apical dendrites of layer 5 neurons propagate several

Spatial distribution of synaptic inputs: functional clustering

Initiation of dendritic spikes is critically dependent on the spatial distribution of synchronously active synapses. For spikes to initiate, synchronously activated synaptic inputs must be spatially clustered in the same dendritic segment. In contrast, distributed dendritic inputs are not efficient at initiating local dendritic spikes [39]. At present, we have few experimental data concerning the spatial innervation pattern of synapses, and whether inputs tend to cluster according to the

Dendritic spikes in vivo

NMDAR channels have been shown to be important in information processing in vivo (reviewed in [48]); however, the mechanisms by which NMDAR channels exert their critical effect in vivo remain unknown. We propose that this may be related at least in part to their contribution in nonlinear dendritic processing.

Several recent publications described dendritic spikes in the intact anesthetized rat brain in vivo. These include local Ca2+ spikes in the apical dendrites of pyramidal neurons in the

Conclusions

Local dendritic spikes are a powerful amplification mechanism for synchronously activated clustered synaptic activity. Here we have highlighted the unique role of NMDAR channels in the initiation of local dendritic spikes. Although the past few years has increased our knowledge of the role of NMDAR channels in synaptic processing, many questions remain unanswered. Do NMDA spikes occur in vivo and under what conditions? How do NMDA spikes participate in shaping the output of the neuron? What is

Acknowledgement

We thank M Hausser, ME Larkum and BW Mel for reading a version of the manuscript. In addition we thank G Major for reading the manuscript, providing Fig. 1 and associated text, and for many stimulating discussions. Part of the work presented was supported by the GIF foundation (to J Schiller).

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

References (55)

  • D Johnston et al.

    Active properties of neuronal dendrites

    Annu Rev Neurosci

    (1996)
  • J Magee et al.

    Electrical and calcium signaling in dendrites of hippocampal pyramidal neurons

    Annu Rev Neurosci

    (1998)
  • M Hausser et al.

    Diversity and dynamics of dendritic signaling

    Science

    (2000)
  • L.J Cauller et al.

    Synaptic physiology of horizontal afferents to layer I in slices of rat SI neocortex

    J Neurosci

    (1994)
  • R Lipowsky et al.

    Dendritic Na+ channels amplify EPSPs in hippocampal CA1 pyramidal cells

    J Neurophysiol

    (1996)
  • T Gillessen et al.

    Amplification of EPSPs by low Ni2+- and amiloride-sensitive Ca channels in apical dendrites of rat CA1 pyramidal neurons

    J Neurophysiol

    (1997)
  • J.C Magee et al.

    A synaptically controlled, associative signal for Hebbian plasticity in hippocampal neurons

    Science

    (1997)
  • D.A Hoffman et al.

    K+ channel regulation of signal propagation in dendrites of hippocampal pyramidal neurons

    Nature

    (1997)
  • M Margulis et al.

    Temporal integration can readily switch between sublinear and supralinear summation

    J Neurophysiol

    (1998)
  • L Nowak et al.

    Magnesium gates glutamate-activated channels in mouse central neurones

    Nature

    (1984)
  • G.L Collingridge et al.

    Frequency-dependent N-methyl-d-aspartate receptor-mediated synaptic transmission in rat hippocampus

    J Physiol

    (1988)
  • A.M Thomson et al.

    Voltage-dependent currents prolong single-axon postsynaptic potentials in layer III pyramidal neurons in rat neocortical slices

    J Neurophysiol

    (1988)
  • K.A Clark et al.

    Evidence that heterosynaptic depolarization underlies associativity of long-term potentiation in rat hippocampus

    J Physiol (Lond)

    (1996)
  • A.M Thomson

    Activity-dependent properties of synaptic transmission at two classes of connections made by rat neocortical pyramidal axons in vitro

    J Physiol (Lond)

    (1997)
  • A.U Larkman

    Dendritic morphology of pyramidal neurones of the visual cortex of the rat: III Spine distributions

    J Comp Neurol

    (1991)
  • P.C Schwindt et al.

    Amplification of synaptic current by persistent sodium conductance in apical dendrite of neocortical neurons

    J Neurophysiol

    (1995)
  • P.C Schwindt et al.

    Local and propagated dendritic action potentials evoked by glutamate iontophoresis on rat neocortical pyramidal neurons

    J Neurophysiol

    (1997)
  • Cited by (0)

    View full text