ReviewNMDA receptor-mediated dendritic spikes and coincident signal amplification
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)
- et al.
Dendritic integration in mammalian neurons, a century after Cajal
Neuron
(1996) - et al.
Action potential initiation and backpropagation in neurons of the mammalian CNS
Trends Neurosci
(1997) - et al.
Dendritic signal integration
Curr Opin Neurobiol
(1997) - et al.
EPSPs in rat neocortical pyramidal neurones in vitro are prolonged by NMDA receptor-mediated currents
Neurosci Lett
(1992) - et al.
Linear summation of excitatory inputs by CA1 pyramidal neurons
Neuron
(1999) - et al.
Dendritic sodium spikes are variable triggers of axonal action potentials in hippocampal CA1 pyramidal neurons
Neuron
(1998) - et al.
Impact of active dendrites and structural plasticity on the storage capacity of neural tissue
Neuron
(2001) - et al.
Stability of the memory of eye position in a recurrent network of conductance-based model neurons
Neuron
(2000) - et al.
Intrinsic function of a neuronal network — a vertebrate central pattern generator
Brain Res Brain Res Rev
(1998) - et al.
Functional role of plateau potentials in vertebrate motor neurons
Curr Opin Neurobiol
(1998)