Cell Tissue Res (2006) 326:369–377
DOI 10.1007/s00441-006-0263-8
REVIEW
Dendritic spikes and activity-dependent synaptic plasticity
Knut Holthoff & Yury Kovalchuk & Arthur Konnerth
Received: 7 April 2006 / Accepted: 31 May 2006 / Published online: 1 July 2006
# Springer-Verlag 2006
Abstract Whereas the regenerative nature of action poten-
tial conduction in axons has been known since the late
1940s, neuronal dendrites have been considered as passive
cables transferring incoming synaptic activity to the soma.
The relatively recent discovery that neuronal dendrites
contain active conductances has revolutionized our view of
information processing in neurons. In many neuronal cell
types, sodium action potentials initiated at the axon initial
segment can back-propagate actively into the dendrite
thereby serving, for the dendrite, as an indicator of the
output activity of the neuron. In addition, the dendrites
themselves can initiate action-potential-like regenerative
responses, so-called dendritic spikes, that are mediated
either by the activation of sodium, calcium, and/or
N-methyl-D-aspartate receptor channels. Here, we review
the recent experimental and theoretical evidence for a role
of regenerative dendritic activity in information processing
within neurons and, especially, in activity-dependent
synaptic plasticity.
Keywords Dendritic spikes . Synaptic plasticity . LTD . LTP
Introduction
Since the pioneering work of Ramón y Cajal (1904), the
diversity in the morphology of neuronal cells has fascinated
This work was supported by grants from the Deutsche
Forschungsgemeinschaft.
K. Holthoff (*) : Y. Kovalchuk : A. Konnerth
Institute of Neuroscience, Technical University Munich,
Biedersteinerstrasse 29,
80802 Munich, Germany
e-mail: knut.holthoff@lrz.tu-muenchen.de
generations of neuroscientists. Indeed, the identification of
the link between the structure and specific function of the
various types of neurons remains an ongoing challenge.
More than a century ago and without detailed physiological
knowledge, Ramón y Cajal postulated correctly that
dendrites and axons serve as the anatomical correlates of
the input and the output devices of neurons, respectively
(Ramón y Cajal 1891). Thereafter, as a result of more
detailed investigations, dendrites were compared with a
telephone switchboard, a tree of passive electrical cables, or
a digitally computing unit (for a review, see Yuste and Tank
1996). One of the truly groundbreaking observations in the
field of dendritic physiology was the discovery of a variety
of active conductances in neuronal dendrites (for reviews,
see Johnston et al. 1996; Häusser et al. 2000; Reyes 2001).
This suggested that dendrites not only modulated postsyn-
aptic potentials on their way to the soma (Magee and
Johnston 1995; Cash and Yuste 1999), but that they could
also of themselves cause spike-like activity (Fig. 1). So far,
three major types of dendritic action potentials (also called
dendritic spikes) have been characterized; they are mediat-
ed by the regenerative activation of either sodium, calcium,
or N-methyl-D-aspartate (NMDA) receptor channels and
are therefore called sodium, calcium, or NMDA spikes,
respectively. Here, we review the possible roles of these
different forms of regenerative activity in neuronal den-
drites for the integration of synaptic input, with special
emphasis on processes of activity-dependent synaptic
plasticity.
Back-propagating sodium action potentials
Whether one or multiple initiation zones exist for regener-
ative activity in neurons has long been debated. Early
370
Fig. 1 Synaptically evoked dendritic spikes in cortical layer V
pyramidal neuron. a Camera lucida drawing of a layer V pyramidal
neuron in the mouse visual cortex and the experimental configuration.
Whole-cell recordings were obtained in the current clamp mode, and
cells were filled with 200 μM low-affinity calcium indicator dye
(Oregon-Green BAPTA-6F) via the patch-pipette. Imaging was
performed with a Noran confocal microscope. The neurons were
stimulated synaptically by single electrical shocks via an extracellular
electrode placed in the vicinity of a dendrite. b Top Strong synaptic
stimulation evoked a local dendritic spike accompanied by a calcium
transient in the activated dendrite (upper trace), and a complex
excitatory postsynaptic potential (EPSP) was recorded at the soma
(lower trace). Bottom Pseudo-color coded image of the relative
change in fluorescence in a basal dendrite after dendritic spike
initiation. Images were derived from a movie sequence obtained under
conditions of weak confocality (large confocal slit size, 20× objective)
to allow visualization of dendrites at different focal planes. Modified
from Holthoff et al. (2004)
experiments in the 1950s involving intracellular recordings
of spinal motoneurons suggested that sodium action
potentials were initiated in the axon (Coombs et al. 1957;
Fatt 1957; Fuortes et al. 1957). This view was supported by
subsequent work with extracellular recordings (Hounsgaard
and Yamamoto 1979; Jefferys 1979; Miyakawa and Kato
1986; Richardson et al. 1987; Buzsaki et al. 1996; Buzsaki
and Kandel 1998), but the results also depended on the cell
type examined (Zecevic 1996; Djurisic and Zecevic 2005;
Stuart and Sakmann 1994; Häusser et al. 1995; Spruston et
al. 1995; Larkum et al. 1996). Recent work utilizing
voltage-sensitive-dye imaging has identified more precisely
the axon initial segment as the trigger zone for sodium
action potentials in layer V pyramidal neurons (Palmer and
Stuart 2006). Interestingly, the experiments with simulta-
neous patch clamp recordings from multiple cellular
Cell Tissue Res (2006) 326:369–377
regions have clearly shown that sodium action potentials
initiated close to the soma not only propagate along the
axon, but also actively invade the dendritic tree (Stuart and
Sakmann 1994; Spruston et al. 1995; Larkum et al. 1996).
In the main apical dendrite of mitral cells of the olfactory
bulb and in dopaminergic cells of the substantia nigra,
back-propagating action potentials do not attenuate along
their path into the dendrite at all (Bischofberger and Jonas
1997; Chen et al. 1997; Häusser et al. 1995), reflecting a
highly regenerative mode of propagation. In most other cell
types, however, including cortical and hippocampal pyra-
midal neurons, back-propagation of sodium action poten-
tials is less effective and results in a decrease in amplitude
with the distance from the soma (for reviews, see Stuart et
al. 1997b; Waters et al. 2005). One extreme example is the
cerebellar Purkinje cell, which does not show any active
sodium action potential back-propagation, because of a low
sodium channel density in its dendrites (Stuart and Häusser
1994).
Many other factors determine the effectiveness of
sodium action potential back-propagation including the
branching pattern of the dendrite (Spruston et al. 1995;
Vetter et al. 2001), the density and distribution of
potassium conductances (Hoffman et al. 1997; Migliore
et al. 1999), the resting membrane potential (Waters and
Helmchen 2004), the rate of action potential firing
(Spruston et al. 1995; Callaway and Ross 1995; Larkum
et al. 1999), the action potential width (Häusser et al.
1995; Golding et al. 2001), and the excitatory (Hoffman et
al. 1997; Magee and Johnston 1997; Pan and Colbert
2001; Stuart and Häusser 2001) and the inhibitory
(Buzsaki et al. 1996; Chen et al. 1997; Larkum et al.
1999) synaptic background activity.
The physiological relevance of sodium action potential
back-propagation has been the center of controversial
discussions, because evidence from early studies in vivo
suggests only passive invasion occurs into the dendrites of
cortical layer II/III pyramidal neurons (Svoboda et al. 1997,
1999). However, later studies, in part directly comparing
the in vitro and in vivo conditions in the same cortical
region, have provided convincing evidence for an active
back-propagation of action potentials also in vivo (Buzsaki
et al. 1996; Helmchen et al. 1999; Waters et al. 2003;
Waters and Helmchen 2004).
What is the putative physiological function of back-
propagating sodium action potentials, and why is the
efficacy of back-propagation of distinct scientific interest?
The cellular basis of learning and memory is widely
accepted as being in part attributable to the ability of the
nervous system to alter the strength or the efficacy of
synaptic connections between neurons. In a highly influen-
tial book, Donald Hebb has postulated (Hebb 1949) that the
synaptic connection between neuron A and neuron B is
Cell Tissue Res (2006) 326:369–377
strengthened, if the firing of neuron A repeatedly leads to
the firing of neuron B. In this context, the back-propagating
action potential in the postsynaptic cell (neuron B) could
serve as a global feedback signal for the dendrite with
regard to the output firing activity of its own axon. This
would enable the neuron to correlate its input activity with
the resulting output, a prerequisite of the Hebbian form of
learning. A recent and popular variation of a Hebbian form
of synaptic plasticity is the so-called spike-timing-depen-
dent plasticity (STDP; for reviews, see Tsodyks 2002;
Roberts and Bell 2002; Dan and Poo 2004).
Spike-timing dependent plasticity
In their pioneering work on cortical pyramidal neurons,
Markram, Sakmann, and colleagues discovered that the
pairing of a synaptic input (i.e., excitatory postsynaptic
potentials, EPSPs) with an action potential, fired during a
narrow time window of several tens of milliseconds in the
same cell, produces a long lasting change in the efficacy of
synaptic transmission (Markram et al. 1997). The direction
of the change in synaptic transmission was shown to be
dependent on the sequential order of the two events, with a
millisecond time precision. If the EPSP comes first and the
postsynaptic action potential follows within a time window
of typically less than 20 ms, long term potentiation (LTP) of
synaptic transmission efficacy is induced. If the order is
reversed, long term depression (LTD) is observed. The
phenomenon of STDP has subsequently been confirmed in
a wide variety of preparations in vitro and in vivo (Zhang et
al. 1998; Bi and Poo 1998; for a review, see Dan and Poo
2004).
Regardless of the mechanisms for induction, one major
player in the expression of synaptic plasticity is the increase
in the postsynaptic calcium concentration during induction
(Lynch et al. 1983; Malenka 1991). Whether a strengthen-
ing or weakening of synaptic transmission is obtained
depends on the amplitude and/or duration of the postsyn-
aptic calcium transient during induction (Sjostrom and
Nelson 2002). The “threshold-hypothesis” proposes that
long-lasting and moderate calcium elevations induce LTD,
whereas short and high increases favour LTP (Lisman
1989; Artola and Singer 1993; Hansel et al. 1997). So far,
however, quantitative estimates of the calcium signals
underlying the induction of LTD or LTP remain unavail-
able, despite numerous attempts over the past few years
(Connor et al. 1999; Conti and Lisman 2002; Malenka et al.
1992; Neveu and Zucker 1996b; Yang et al. 1999; Wang et
al. 2000; Cho et al. 2001; Cormier et al. 2001; Ismailov et
al. 2004).
The postsynaptic NMDA receptor (NMDA-R) has
been identified as the molecular device of the coinci-
371
dence detection underlying STDP. Because it is perme-
able for calcium, and because its blockage by Mg2+ at
resting membrane potentials can be unblocked by post-
synaptic depolarization, the NMDA-R is considered to be
the ideal candidate for detecting the coincidence between
pre- and postsynaptic activity and for translating it into a
postsynaptic calcium transient. Indeed, compared with
synaptic activation and postsynaptic action potential firing
alone (Fig. 2a and b), the pairing of both events in the
right order leads to a supralinear summation of the
postsynaptic calcium transients (Köster and Sakmann
1998; Yuste et al. 1999; Nevian and Sakmann 2004;
Fig. 2c and d). If synaptic activation occurs first, a
subsequent action potential arriving at the activated
synapse within a well-defined time windows can remove
the Mg2+-ion-blocking action of the NMDA-R channel
and, because glutamate is still bound, it will mediate a
large calcium influx. Vice versa, if the action potential
arrives at the synapse before glutamate is released
presynaptically, the NMDA-R channels will remain
largely blocked by the Mg2+ ions, resulting in a moderate
postsynaptic calcium increase.
The mechanisms of the induction and expression of
STDP have been studied extensively, but the precise
mechanisms have not entirely been clarified. Thus,
although initially introduced to be simply timing-depen-
dent, the various pairing protocols for LTP induction have
to be applied repeatedly and at sufficiently high frequen-
cies, otherwise they are not efficient in inducing LTP.
This suggests the notion that pairing alone is not
sufficient to induce LTP (Sjostrom et al. 2001; for
reviews, see Sjostrom and Nelson 2002; Lisman and
Spruston 2005). Whether this rate-dependence of STDP
reflects the need for an additional depolarizing component
besides the back-propagating action potential is not clear.
Nevertheless, in most studies dealing with STDP, the
back-propagating action potentials are induced by somatic
current injections into the postsynaptic cell. These action
potentials ride on a depolarizing wave, which by itself
might support the LTP induction process (Lisman and
Spruston 2005). Furthermore, whether action potential
back-propagation is as effective in vivo as it is in slices
(see above) remains doubtful. However, this concern may
represent an advantage, because the limited efficacy of
action potential back-propagation leaves room for an
elaborated modulatory system determining the parts of
the dendritic tree that will participate in Hebbian learning
(Magee and Johnston 1997; Migliore et al. 1999). In
conclusion, STDP as a model of associative synaptic
plasticity remains an attractive concept, but its physiolog-
ical significance for in vivo conditions is just beginning to
emerge and needs further validation (Lisman and Spruston
2005).
372 Cell Tissue Res (2006) 326:369–377

Fig. 2 Supralinear summation

of postsynaptic calcium tran-
sients in spines by pairing
EPSPs with back-propagating
action potentials. a Weak syn-
aptic stimulation of a layer V
pyramidal neuron in the mouse
visual cortex leads to calcium
transients in an individual spine.
The camera lucida drawing of
the cell (left) shows the experi-
mental configuration (see also
legend to Fig. 1). The color-
coded image (middle) shows the
relative change in fluorescence
at the peak of the calcium
transient. The traces (right) rep-
resent the time course of the
calcium transients analyzed in
the activated spine head (red
traces) and the adjacent dendrite
(black traces). Imaging was
carried out at 125 Hz by
using a Nipkow-disc scanner
(PerkinElmer, Boston) com-
bined with a fast charge-coupled
device camera (Redshirt,
Decatur). b Time courses of
calcium transients in spine and
adjacent dendrite of another cell
following weak synaptic stimu-
lation (upper traces) and back-
propagating action potentials
(lower traces). c Calcium tran-
sients in spine and adjacent
dendrite of the same cell as in
b following the pairing of syn-
aptic stimulation and back-
propagating action potentials
with different pairing intervals.
d Analysis of the pairing-
induced peak calcium ampli-
tudes in spines depending on the
time interval of pairing. Data
were normalized to the peak
calcium amplitude following
synaptic stimulation alone
(n=4 cells)

Local dendritic spikes and information processing
The first evidence that dendrites themselves might generate
regenerative activity probably came from experiments in
hippocampal pyramidal neurons showing small all-or-none
spikelets called fast pre-potentials (FPPs) preceding somatic
action potentials (Spencer and Kandel 1961). Although the
FPPs were subsequently considered to be an artifact of
somatic action potentials fired from electrically coupled
neighboring cells, there is now evidence that dendrites can
indeed initiate all-or-none action potentials in vitro (Houns-
gaard and Yamamoto 1979; Regehr et al. 1993; Golding and
Spruston 1998; Schiller et al. 2000; Wei et al. 2001; Golding
et al. 2002; Polsky et al. 2004; Holthoff et al. 2004) and in
vivo (Pockberger 1991; Hirsch et al. 1995; Kamondi et al.
1998). Based on their electrophysiological properties, two
main classes of dendritic spikes can be distinguished. The
conventional fast spikes are mediated by the regenerative
activation of voltage-sensitive sodium channels, can be
initiated by dendritic current injection (Stuart et al. 1997a) or
Cell Tissue Res (2006) 326:369–377
synaptic stimulation (Turner et al. 1991; Golding and Spruston
1998), and are sensitive to the sodium channel blocker
tetrodotoxin (TTX). On the other hand, the so-called complex
or long-lasting dendritic spikes are mainly caused by the
activation of voltage-dependent calcium and/or NMDA-R
channels and are, therefore, referred to as “calcium spikes”
(Schiller et al. 1997) and “NMDA spikes”, respectively
(Schiller et al. 2000; Schiller and Schiller 2001; for a review,
see Holthoff 2004).
The ability of dendrites to initiate locally regenerative
activity, such as calcium spikes or NMDA spikes, considerably
enriches the repertoire of dendritic integration of synaptic
input. Whereas a linear or sublinear summation of postsynaptic
potentials has been described for distributed synaptic input in
various preparations (Urban and Barrionuevo 1998; Cash and
Yuste 1998, 1999; Magee 2000; Polsky et al. 2004), spatially
clustered synaptic input to the same neurons can induce non-
linear responses in small dendritic sections (Polsky et al.
2004; Holthoff et al. 2004; Losonczy and Magee 2006;
Fig. 1b). Depending on the spatial distribution and timing of
the synaptic input, the same neuron can therefore switch
between an essentially linear and highly non-linear mode of
integration. Both modes of integration can be combined,
because the depolarization produced by the local non-linear
integrating at dendritic subunits sum up linearly at the soma
(Polsky et al. 2004). Simulations suggest that the equipment
of dendrites with non-linearly acting subunits leads to an
increase in potential storage capacity by several orders of
magnitude (Poirazi and Mel 2001). In addition, the alliance of
non-linear and linear integration modes combines the
advantages of the excellent signal-to-noise ratio of digital
processing with the speed and complexity of analog process-
ing in a single cellular compartment, viz., the dendritic tree.
Local dendritic action potentials and synaptic plasticity
A common feature of local dendritic calcium spikes or
NMDA spikes is that they are accompanied by a transient
increase in intracellular calcium concentration (Schiller et al.
1997, 2000; Golding et al. 2002; Wei et al. 2001; Holthoff et
al. 2004). Assuming that the intracellular calcium concen-
tration transient is necessary and sufficient to induce synaptic
plasticity (Neveu and Zucker 1996a), then synaptically
evoked local dendritic spikes can be postulated to be able
to induce synaptic plasticity (Goldberg et al. 2002). Indeed,
two recent reports show that, in hippocampal CA1 neurons
and cortical pyramidal neurons, locally restricted dendritic
spikes on their own can induce LTP and LTD, respectively.
Golding and colleagues (2002) have demonstrated, in an
elegant study, that synaptically evoked dendritic spikes
induce LTP in hippocampal CA1 neurons. This form of
synaptic plasticity does not need active back-propagation of
373
somatic sodium action potentials, because they are blocked
by local application of the sodium channel antagonist TTX to
the proximal part of the apical dendrite. The authors have
convincingly shown that there is a strong correlation between
the incidence of dendritic spike firing and the successful
induction of LTP. In layer V pyramidal neurons of mouse
visual cortex, local dendritic spikes can be induced by strong
extracellular synaptic stimulation (Holthoff et al. 2004;
Polsky et al. 2004) or glutamate uncaging (Schiller et al.
2000; Wei et al. 2001). Surprisingly, the synaptic activation of
a single dendritic spike is sufficient to induce a LTD of excit-
atory synaptic transmission (Holthoff et al. 2004; Fig. 3a,b).
This form of LTD, called single-shock LTD, does not need
somatic spiking and is largely saturated following single-
shock induction. The production of five consecutive dendritic
spikes has no substantial boosting effect (Fig. 3c). Prelimi-
nary results from the same preparation indicate that coinci-
dent pairing of a synaptically evoked dendritic spike with
back-propagating action potentials may evoke a supralinear
increase in the amplitude of the intra-dendritic calcium
transient and subsequently lead to LTP (Holthoff et al.
2005). Thus, mounting evidence indicates that local dendritic
spikes are able to induce bidirectional synaptic plasticity.
What is the computational and physiological significance of
local spike-evoked synaptic plasticity? Unlike STDP, which
requires the coincidence between pre- and postsynaptic
spiking, local spike-evoked plasticity involves the coinci-
dence of synaptic activation of closely grouped inputs to the
same part of a dendrite (Polsky et al. 2004; Losonczy and
Magee 2006). This represents a new learning rule. The new
mechanism divides neurons into largely independent modules
of integration and learning that do not depend on the usual
feedback signal from the soma, viz., the back-propagating
sodium action potential. A major difference between STDP
and local spike-evoked plasticity is the induction speed. Thus,
whereas STDP requires many repetitions of the conditioning
pre-post stimulation (Bear and Abraham 1996; Lisman and
Spruston 2005), a single local spike is sufficient for LTD
(Holthoff et al. 2004) or LTP (Holthoff et al. 2005; but see
Golding et al. 2002) induction. The increased induction speed
largely relies on the synergistic cross-activation of neighbor-
ing NMDA receptor channels located on the same dendrite
(Schiller et al. 2000; Holthoff et al. 2004). Therefore, local
spike-dependent plasticity may be the primary mechanism
underlying the rapid acquisition of memories.
Conclusions and perspectives
During the last few decades, the active properties of neuronal
dendrites have come into the realm of scientific interest.
Parallel to the capability of dendrites for analog computation,
the non-linear processing of synaptic inputs provides modular
374 Cell Tissue Res (2006) 326:369–377

a before after c before after

LTD induction signal

150
n=7

EPSP ampl (%)

Ca V
100
5
EPSP ampl (mV)

50
4
5x
3
0
2
0 10 20 30 40
1 1x
Time (min)
0
before after
0 10 20 30 40 50 60 d
Time (min)

b 150
n=8
150
n=4
EPSP ampl (%)

EPSP ampl (%)

100 100

50 50
1x 5x
0 0
0 10 20 30 40 50 60 0 10 20 30 40
Time (min) Time (min)

Fig. 3 A single local dendritic spike induces instantaneous long-term
synaptic depression (LTD). a Induction of LTD by single dendritic
spike in a pyramidal neuron from layer 5 of the mouse hippocampus
(LTDx1). Synaptic input to a basal dendrite located approximately
50 μm away from the cell body. Note the framed LTD induction signal
(bars 50% ΔF/F, 250 ms for calcium signal and 5 mV, 50 ms for
EPSP). Traces indicate mean EPSPs before and after the conditioning
stimulus (bars 2 mV and 50 ms). b Summary LTDx1 experiments of
eight cells. c LTD induced by five consecutive conditioning stimuli
delivered 15 s apart from each other. d Same experiments as in c, but
cells were hyperpolarized to –80 mV during conditioning stimuli to
prevent the initiation of local dendritic spikes. No significant change
in strength of synaptic transmission was detected. Modified from
Holthoff et al. (2004)

integration, which increases the memory capacity of neuronal
tissue (Poirazi and Mel 2001) and enriches the processing
complexity of dendrites by an implementation of additional
local learning rules (Golding et al. 2002; Holthoff et al.
2004). Although the ability of neuronal dendrites to initiate
local dendritic spikes has been known for several years,
surprisingly few attempts have been undertaken to investi-
gate their ability to induce synaptic plasticity. This may be
because dendritic spikes are often barely detectable by
somatic recordings, making necessary the more difficult
dendritic recordings or imaging techniques to pinpoint the
initiation of dendritic spikes with respect to the induction of
synaptic plasticity (Golding et al. 2002; Holthoff et al. 2004).
Because a single dendritic spike, and therefore a single
postsynaptic calcium transient, is able to induce long-term
synaptic plasticity, the detailed characterization of the
postsynaptic signals that lead to the potentiation or the de-
pression of a synapse will be possible. In particular, the
expression mechanisms of plasticity and the question of
whether LTP and LTD are expressed at the postsynaptic or
presynaptic site are of great interest. The combination of high
resolution imaging and single synapse stimulation by two-
photon glutamate uncaging could refine this analysis down to
the single synapse level. Early experimental evidence has
indicated that local dendritic spikes can provide a means for
the induction of synaptic plasticity in vitro (Golding et al.
2002; Holthoff et al. 2004, 2005); however, the significance
of this mechanism for in vivo conditions remains obscure.
An important challenge for the future will be to
investigate the physiological significance of local dendritic
signaling for cortical information processing in the
sensory system in vivo and to test whether it participates
in synaptic plasticity during development and learning.
Some of these tests will probably involve the use of
multi-photon imaging (for a review, see Helmchen and
Denk 2005) in combination with various neuron labeling
techniques (Stosiek et al. 2003; Rathenberg et al. 2003;
Miesenböck 2004; Mank et al. 2006).
Cell Tissue Res (2006) 326:369–377
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