Local Plasticity of Dendritic Excitability Can Be Autonomous of Synaptic Plasticity and Regulated by Activity-Based Phosphorylation of Kv4.2
Zhang X (2014) Local Plasticity of Dendritic Excitability Can Be Autonomous of Synaptic Plasticity and Regulated by
Activity-Based Phosphorylation of Kv4.2. PLoS ONE 9(1): e84086. doi:10.1371/journal.pone.0084086
Local Plasticity of Dendritic Excitability Can Be Autonomous of Synaptic Plasticity and Regulated by Activity-Based Phosphorylation of Kv4.2
Anna Labno 0
Ajithkumar Warrier 0
Sheng Wang 0
Xiang Zhang 0
Jean-Luc Gaiarsa, Institut National de la Sante et de la Recherche Medicale (INSERM U901), France
0 1 Nano-scale Science and Engineering Center, Berkeley, California, United States of America, 2 Biophysics Program, University of California Berkeley , California , United States of America
While plasticity is typically associated with persistent modifications of synaptic strengths, recent studies indicated that modulations of dendritic excitability may form the other part of the engram and dynamically affect computational processing and output of neuronal circuits. However it remains unknown whether modulation of dendritic excitability is controlled by synaptic changes or whether it can be distinct from them. Here we report the first observation of the induction of a persistent plastic decrease in dendritic excitability decoupled from synaptic stimulation, which is localized and purely activity-based. In rats this local plasticity decrease is conferred by CamKII mediated phosphorylation of A-type potassium channels upon interaction of a back propagating action potential (bAP) with dendritic depolarization.
Funding: This work is supported by the National Institutes of Health through the NIH Roadmap for Medical Research (PN2 EY018228) and the National Science
Foundation Nano-scale Science and Engineering Center (NSF-NSEC) for Scalable and Integrated NAnoManufacturing (SINAM) (Grant No. CMMI-0751621). The
funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Persistent modifications of neuronal function, in response to
repetitive and precisely timed synaptic stimuli are believed to be
the key mechanism underlying learning, memory formation and
storage . While these modifications are based on the modulation
of synaptic strengths , it is widely believed that different forms of
synaptic plasticity can alter local dendritic excitability by
modulating both resting and voltage-gated channels along the
length of the dendrites [3,4] and that such compartmentalized
dendrites can greatly expand the computational power of a single
neuron . In contrast to alterations of global excitability, which
may occur independently of synapses, localized modulations of
dendritic excitability have never been observed in the absence of
synaptic plasticity . Kv4.2 channels play crucial role in
controlling neuronal excitability by mediating transient A-type
potassium currents [10,11], have been directly associated with
spatial memory in rats  and are implicated in a number of
hyperexcitability and neurodegenerative diseases such as epilepsy
[11,1315], ischemia [16,17] and Fragile X mental retardation
[18,19]. Up to date dendritic patch clamp recordings were used to
study localized changes of dendritic excitability. However it
is challenging to use dendritic recordings to study localized
excitability in multiple different cellular compartments of the same
cell with high spatiotemporal resolution due to difficulty of
patching more than a couple of cellular sites at the same time and
inability to relocate the patch site, thus leaving key questions about
the role of dendritic excitability in plasticity unsolved. Is dendritic
excitability contingent upon synaptic processes or can dendrites
detect activation patterns independently? What role do active
dendrites play in memory storage and in facilitating synaptically
based storage? What mechanisms regulate Kv4.2 channel
phosphorylation and localization?
Materials and Methods
Cell culture and Transfection
Animal euthanasia procedures were conducted according to
guidelines approved by the Office of Laboratory Animal Care
(OLAC) Committee on Laboratory and Environmental Biosafety
University of California, Berkeley, which approved this study.
Animals (neonatal rats) are obtained from the Animal facility, and
decapitated after brief carbon dioxide anesthesia. Hippocampi
were dissected from P1-2 Sprague Dawley rats of either sex, and
kept in ice-cold HEPES buffered Hanks Balanced Salt Solution
(HBSS, GIBCO) at all times. Cells were dissociated with trypsin
for 10 min at 37uC, followed by gentle trituration. The dissociated
cells were then transfected with pcDNA3.1/hChR2-EYFP (kind
gift from Karl Deisseroth, sequence can be found in the every
Vecotr depository (http://www.everyvector.com/sequences/show_
public/2498) to allow for transient photodepolarization of dendritic
membrane  using Nucleofector-II (Amaxa Biosystems) in
accordance with manufacturers protocol (1) and plated at a density
of 25,00050,000/cm2 on poly-l-lysine-coated glass coverslips.
Dissociated neurons were cultured in Neurobasal medium (GIBCO)
supplemented with B-27 (Invitrogen) and penicillin-streptomycin
(10U/ml, GIBCO). Experiments were done on morphologically
identified pyramidal neurons 1418 d in vitro (DIV).
Hippocampal neurons were placed in a perfusion chamber and
visualized using inverted Nikon TE-2000E microscope and Andor
EM-CCD (Andor). The cell plane was illuminated with X-Cite
120 lamp (Lumen Dynamics) and only neurons, which expressed
EYFP, were chosen for experiments. To generate patterned
illumination, a 470 nm LED (Phillips) was expanded, collimated
and reflected directly from digital mirror device (DMD, InFocus
LP435Z) coupled into the microscope (Fig. 1 B). The diode was
synchronized with electrical stimulation through a TTL signal to
provide step on/off light stimulus and DMD was controlled using
VGA signal from a computer. DMD patterns were generated via
custom written MATLAB (Mathworks) software, which allowed
user to position an arbitrary light pattern over the displayed cell
image. For a majority of the experiments, a circular pattern of
28 um in diameter was positioned over the imaged proximal
section of the dendrite. Somatic and whole cell measurements
(shown in Fig. 2 B and D) were measured analogously to dendritic
excitability but rather than photostimulating the dendrite we
photo-stimulated soma or the entire cell respectively. A set of
previously determined affine transformations were applied to the
pattern, so that after passing through the optical path of the
microscope, it would be correctly positioned with respect to the
cell. To stimulate the cell we paired thirty 2s photocurrent
injections (or 100 ms in case of data presented in Figure 2) at
0.2 Hz which caused sub-threshold depolarization, into proximal
dendritic compartment, with APs (20 ms after the onset of the
light), which were evoked by depolarizing the cells to
approximately +40 mV for 10 ms.
Individual coverslips were placed in a recording chamber
(Biosciences) and submerged in room temperature ACSF
(145 mM NaCl, 3 mM KCl, 10 mM HEPES, 20 mM glucose, 2
CaCl2 and 1 MgCl2) supplemented with 0.1 mM picrotoxin
(Sigma), 0.01 mM DNQX (Sigma) at 322 mOsm, pH 7.4. Voltage
or current clamp recordings were performed in the perforated
somatic patch-clamp configuration. Electrodes (25 MV) were
pulled from borosilicate glass tubing (World Precision Instruments)
using a laser based micropipette puller (Sutter Instrument P-2000).
The pipette tip was dipped in an intracellular solution containing
(in mM) 68 K-gluconate, 68 mM KCl, 0.2 mM EGTA, 2
MgSO4, 20 HEPES, 3 ATP, 0.2 mM GTP (322 mOsm, pH
7.4) and then backfilled with the same solution but containing
0.12 mg/ml amphotericin B (Sigma); final osmolarity was about
290 mOsm/kg H2O and open pipette resistance when filled was
25 MV. A stable perforated patch was obtained after 1520 min
incorporation time. The access resistance was ,1540 MV and to
minimize the effect of access resistance change on measured
current we only recorded cells which showed small variations of
access resistance (less than 5%) through the entire experiment.
Currents were recorded using patch-clamp amplifier Axopatch
200B-2 in conjunction with Digitizer 1440A, sampled at 10 kHz.
The holding potential in voltage-clamp mode was 270 mV,
uncorrected for any liquid junction potential between internal and
external solutions. All the experiments were conducted in voltage
clamp except the DED stimulation and measurement of
spikecurrent relationship, which was conducted in current clamp.
Intrinsic excitability was measured by applying 2 s depolarizing
current pulses in increasing current increments (0.1-nA
increments) and at each depolarizing step, the number of evoked action
potentials was counted and plotted against injected current
amplitude . Recordings were analyzed using pClamp v10
software or custom written Matlab code. Whenever % decrease is
mentioned in the text it refers to the difference between averaged
excitability over the entire duration of the experiment before and
after stimulation typically 510 min. For pharmacological
experiments all drugs were obtained from Sigma-Aldrich with
an exception of Stromatotoxin-II which was obtained from Alome
Labs. All drugs were bath applied and handled according to
Immunofluorescence staining of neurons
Dendritic excitability decrease was induced as described in the
methods section above with the exception that DED stimulation
was Thirty trains of stimuli were delivered using Iso Flex Unit
Stimulator (A.M.P.I) rather than patch pipette (AMPI Jerusalem,
Israel). Two elongated electrodes delivered these 10 ms stimuli to
the culture. The voltage drop across the preparation was
approximately 70V and we confirmed that this stimulus was
capable of robustly inducing spiking. Cells were fixed immediately
after stimulation with 4% paraformaldehyde (Sigma) in PBS for
20 minutes before being permeabilized (1% Triton-X, Sigma) and
blocked in block solution (PBS containing 5% BSA). Then cells
were incubated for 4 h with anti-pKv4.2 Ser 438 monoclonal
antibodies (Santa Cruz Biotechnology) and then Alexa Fluor 568
secondary antibodies (Invitrogen). Coverslips were mounted using
Fluoromount-G (SouthernBiotech) and sealed with nail polish.
Cells were visualized using a Nikon TE-2000 inverted
epifluorescence microscope through 6060.8 NA Nikon or 10061.3NA Zeiss
objective. Images were digitally captured using EMCCD Andor.
Excitation was via X-Cite lamp with appropriate filter cubes.
Images were analyzed using ImageJ and custom written Matlab
The dendritic excitability was assessed by measuring the peak of
the photocurrent at each stimulation over time [8,10] except for
the first two stimulations in each experiment, which were removed
because at that time ChR2 hasnt reach steady state
desensitization level. The data were normalized by taking the averaged
excitability measured before the stimulation to be 100% and then
normalizing each indyvidual excitability measurement (both
before and after stimulation) to that. Significance of differences
between the excitability before and after the stimulation was tested
with two tailed heteroscedastic Students t-test, except of the
spikecurrent data and pharmacological data (Fig. 3), which were tested
using ANOVA test with Tukey post hoc comparison, and p,0.05
was considered as significant. Throughout the paper dendritic
excitability changes are given as mean 6 standard error on the
mean and n = no/no indicates number of cells/number of
experiment; asterisk, p,0.05; double asterisk, p,0.01; triple
asterisk, p,0.001. The images of immunostaining against Kv4.2
phosphoylated at Ser 438 were analyzed by first normalizing all
the images to account for differences in light intensity by dividing
each pixel in the image by its average intensity. Then the image of
the dendrite was straighten using ImageJ Plugin (Straighten, )
and average fluorescence along the dendrite was calculated by
drawing a line through the center of the dendrite and calculating
average along this line. In each cell, stimulated dendrite and
another dendrite with comparable amount of YFP staining were
chosen for analysis. If there werent any unstimulated dendrites
that have similar amount of YFP as the simulated one the cell was
not used for analysis. Significance of differences between the
fluorescence in stimulated and unstimulated dendrites was tested
with unpaired Students t-test.
Figure 2. DED is spatially localized. (A, B, C and D) Top panels display the dendritic location used for dendritic stimulation (blue circle) and the
range of possible report locations (white dotted lines). Bottom panels show example current measurements before (black) and after stimulation (grey
or blue) as well normalized current before and after stimulation. Following proximal dendritic stimulation, (A) proximal dendritic current decreases
(DED = 2.94%62.19%, p,001, n = 11/12) (B) somatic current shows increase in excitability by 4.89%61.89 (p,0.001 n = 10/10) (C) Un-stimulated
dendrites dont show DED (%DED = 0.05%62.93%, p = 0.22, n = 10/10) and (D) Current resulting from whole cell photo-stimulation does not change
significantly (DED = 20.4%61.9, n = 9/9, p = 0.10).
HpTx EGTA U0126
To understand the contribution of activity to plasticity of
dendritic excitability we developed a technique to decouple the
dendritic excitability changes from synaptic strength changes by
stimulating dendrites with a protocol similar to spike timing
dependent plasticity (STDP) substituting presynaptic cell
stimulation with localized photostimulation of ChR2 using a digital
micromirror device (DMD). The use of a DMD allowed us to
photostimulate multiple sub-cellular locations simultaneously and
to vary the locations of the depolarizations with millisecond
resolution (Fig. 1.a,b) . Synaptic transmission was completely
blocked by a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (AMPA) and gamma-aminobutyric acid (GABA) receptor
antagonists (10 uM DNQX and 100 uM PTX).
Persistent change in dendritic excitability can be induced
independently of synaptic inputs
We observed that even in the absence of synaptic inputs, pairing
thirty 2s photocurrent injections into proximal dendritic
compartment, with APs (20 ms after the onset of the light) resulted in a
persistent (.15 min) decrease in dendritic excitability as indicated
by the decrease of amplitude of evoked current at the soma
(Fig. 1cd, DED = 13%61.7% p,0.001, n = 12/12, no
stimulation = 0.74%62.0% p = 0.35 n = 6/6). We will refer to this
phenomenon as dendritic excitability depression (DED). DED
requires a coincident interaction of dendritic stimulation and APs
and neither APs alone (DED = 0.28%60.98% p = 0.68, n = 7/7)
nor dendritic stimulation alone (DED = 0.1%60.76%, p = 0.88,
n = 6/6) induced DED. Similarly no stimulation of any kind also
does not result in a change of excitability (0.74%62.0% p = 0.35
n = 6/6, Fig. 1e). This suggests that dendrites can detect coincident
dendritic stimulation and APs independently of synaptic AMPA
and GABA receptors. Because DED can only be induced by
coincident dendritic depolarization and AP and not by light
stimulation alone shows that the change in dendritic excitability is
not a result of photo damage due to repetitive photo stimulation.
We observed no change in intrinsic, whole-cell excitability
accompanying DED, as indicated by unchanged Spike-Current
relationship (Fig. 1f, p = 1.00, n = 3/3). This suggests that DED
was the result of localized dendritic excitability modulation.
DED is spatially localized
To investigate how different sub-cellular compartments respond
to DED we induced DED at one of the proximal sites and
measured the excitabilities at other dendrites, soma and
excitability of the entire cell. In this experiment we used 100 ms
stimulation to determine dendritic excitability because prolonged
2s photo-stimulation injected too much current when applied on
the cell body or over the entire cell causing abnormal spiking. First
we stimulated a proximal dendrite and observed a change of
excitability on that dendrite, just as before, but using 100 ms
photo-stimulation. DED was smaller in magnitude but still reliably
induced (Fig. 2a, DED = 2.94%60.63%, p,0.001, n = 11/12).
When the whole cell was photo-stimulated the excitability was not
affected (DED = 20.13%61.0%, n = 10/10, p = 0.98, Fig. 2d),
supporting the observation that intrinsic excitability does not
change. On the other hand the somatic excitability, measured by
somatic current, increased (Fig. 2b increase of 5.23%60.98%,
p,0.001, n = 10/10). Finally unstimulated dendritic branches
were unaffected by the stimulation of another branch (Fig. 2b.
%DED = 0.05%60.93%, p = 0.46, n = 10/10). Taken together,
these results show that DED is confined to a stimulated dendrite
and coupled with modulation of somatic excitability, which might,
akin to homeostatic plasticity, serve to keep overall neuronal
excitability unchanged .
Kv4.2 channels are responsible for DED
Since voltage-gated channels regulate dendritic processing by
dynamically modulating membrane excitability in a spatially
restricted manner [28,29], we tested their involvement in DED.
Figure 4. Kv4.2 phosphorylation is enhanced along the stimulated dendrite. (A) Immunostaining against Kv4.2 phosphoylated at Ser 438
shows enhanced phosphorylation at the stimulated dendrite as compared with the un-stimulated dendrite of the same cell. The dendrites have
comparable amounts of ChR-YFP. Dendrites from two representative cells are shown (top and bottom). The white circles indicate the location of
photostimulation. (B) Mean immunofluorescence of pKv4.2 along the stimulated dendrites is much higher (mean fluorescence = 36.562.84) than
along the non-stimulated dendrites (mean fluorescence = 19.863.17), p = 0.01, n = 5/5.
Application of non-selective voltage-gated potassium channel
inhibitor (20 mM TEA) eliminated most of the DED (DED =
1.47%60.95%, p = 0.08, n = 10/10, Fig. 3e). Stromatotoxin
(100 nM), which specifically inhibits delayed rectifier and A-type
potassium channels  (Kv2.1, Kv4.2, Kv2.2 and Kv2.1/9.3),
significantly reduced DED (Fig. 3e, DED = 1.6%61.0%, p = 0.01,
n = 5/5). To distinguish between Kv2.1 and Kv4.2 channels, we
bath-applied Heteropodatoxin-2 (Hptx, 100 nM) which
specifically blocks Kv4.2, Kv4.1 and Kv4.3 but not Kv2.1 . Hptx
completely eliminated DED (Fig. 3a and e. DED = 20.04%6
0.79%, p = 0.92, n = 10/10). This data indicates that decrease of
dendritic excitability is conferred by changes in A-type potassium
currents mediated by Kv4.2 channels.
Since Kv4.2 channels also control bAPs, we further investigated
whether bAPs are essential for induction of DED. If an interaction
between bAPs and dendritic stimulation is required for DED, then
it is reasonable to assume that abolishing spikes by bath
application of sodium channel blockers should reduce DED
[32,33]. Application of 1 uM tetrodotoxin (TTX) precluded
induction of DED (Fig. 3b,e. DED = 0%62.5%, p = 0.84, n = 5/5),
suggesting that DED requires coincident interaction of bAPs and
Subsequently we wanted to investigate if calcium, which is
essential for many neurological processes, is necessary for DED.
To determine this we attempted to induce DED in 0 Ca2+ with
2 mM EGTA-AM, which can be passively loaded into cells to
chelate intracellular calcium. Dendritic excitability didnt change
with calcium buffered (DED = 0.65%61.8%, p = 0.33, n = 7/7).
Then we turned our attention to MEK, which because MAPK
cascade is known to be able to integrate coincident signals and to
translate the magnitude of signaling into a temporally and spatially
graded response  and has been previously implicated in
learning and memory in behaving animals  and shown to be
necessary for many forms of synaptic plasticity [34,36] and
dendritic excitability regulation  although its precise role is
unknown Blocking MEK using 10 uM of U0126 abolished
induction of DED (DED = 0.07%60.3%, p = 0.93).
Finally, to ensure that DED is not a result of synaptic process
where NMDA receptors are activated by local depolarization and
Glu released from synapses or ambient Glu released from other
synapses in the cleft we induced DED in the presence of NMDA
blocker APV (50 uM). Dendritic excitability decreased 9.1%6
2.0% (p,0.001, n = 5/5) indicating that NMDA receptors are not
involved in DED and that the process is independent of synaptic
Taken together this data suggest DED stimulation induces
interaction of bAP with local dendritic depolarization, which may
increase the level of intracellular calcium. Elevated calcium
activates a signaling cascade involving MEK, which then affects
the Kv4.2 channels leading to an increased A-type current and
MEK regulated CamKII phosphorylation of Kv4.2
To gain further insight into the physical mechanism, that allows
Kv4.2 channels to modulate dendritic excitability dynamically, we
performed immunostaining against Ser 438 phosphorylated
Kv4.2. Ser438 is the site that CamKII specifically phosphorylates
Kv4.2 at. The density of phosphorylated Kv4.2 along the
stimulated dendrite was significantly higher (Fig. 4, increase
16.7%, p = 0.01, n = 5/5) than along a comparable, unstimulated
dendrite on the same cell. This suggests that DED is associated
with differential phosphorylation of Kv4.2. This phosphorylation
increases Kv4.2 current  and may also affects translocation
direction and turnover rate of Kv4.2 [39,40].
Activity dependent modulations in dendritic excitability are
central to information processing and storage but so far have only
been seen in addition to synaptic plasticity. Here we show that
localized depression of dendritic excitability can be decoupled
from synaptic processing. DED cannot be induced by dendritic
photo stimulation alone or APs alone indicating that this change in
dendritic excitability is not an artifact of photo stimulation
resulting in channel damage or persistent somatic stimulation,
but rather it is a persistent physiological change brought about by
coincided dendritic activity.
DED is confined to the stimulated dendrite and brought about
by interaction of bAPs with dendritic depolarization. This
coincidence is detected in NMDA-independent way, possibly via
PKC pathway, which has been previously proposed to regulate
excitability  and serve as a coincidence detector [42,43]. Since
DED is calcium dependent and cannot be induced in the absence
of calcium we hypothesize that this interaction induced increase in
intracellular calcium, which results in MEK-regulated
phosphorylation of Kv4.2 at Serine 438 residue. MEK is known to regulate
Kv4.2 phosphorylation by activating either ERK  or CamKII
[45,46] which can then directly phosphorylate Kv4.2. Inhibition of
MEK interferes with LTP induction [37,47]. CamKII
phosphorylates Kv4.2 at Ser438 while ERK phosphorylates Kv4.2 at T602,
T607, and S616. DED is accompanied by increased levels of
Kv4.2 phosphorylated at Ser438 at the stimulated dendrite,
suggesting that increased calcium causes ERK activation, which in
turn activates CamKII which directly phosphorylates Kv4.2.
Ser438 Kv4.2 phosphorylation leads to increase in local cellular
Kv4.2 and potentiation of A-type current  and hence
decreases dendritic excitability by approximately 12%. During
STDP LTP induction blocking MEK activity reduced the boosting
of the action potential by a similar amount .
While previously redistribution of A-type potassium channels
was shown to accompany various forms of LTP [11,28,38] here we
show for the first time that Kv4.2 channels can self-organize to
locally alter the excitability of the dendrite in the absence of any
signaling resulting from synaptic potentiation. Recently,
compartmentalized branch specific potentiation of dendritic excitability
has been demonstrated following repeated local spike initiation
with transient application of carbachol or theta pairing protocol
. In contrast to DED this stimulation protocol resulted in
potentiation of branch strength which might be due to different
stimulation protocol or likely involvement of synaptic plasticity
. Since A-type K+ currents are the major modulator of
backpropagating action potentials (bAP)  and increase in A-type
current, such as one that could be causing DED, decreases bAP
[50,51], DED may decrease both the bAP  and forward
propagating sub-threshold photocurrent. This would lead to
depression of dendritic current reaching the soma but also limits
further development of DED by decreasing the magnitude of
bAPs. Such compartmentalized and active excitability modulation
can lead to forming privileged and repressed pathways of activity
and may be a general feature of dendritic information storage and
would greatly increase neuronal storage capacity [52,53]. It
suggests that dendrites can play a far more crucial and
independent role than previously believed by self-organizing in
response to activity rather than being synaptically controlled.
Conceived and designed the experiments: AL AW SW XZ. Performed the
experiments: AL AW. Analyzed the data: AL AW. Contributed reagents/
materials/analysis tools: AL AW SW. Wrote the paper: AL AW SW XZ.
1. Kandel ER ( 2001 ) The molecular biology of memory storage: a dialogue between genes and synapses. Science (New York, NY) 294 : 1030 - 1038 . doi:10.1126/science.1067020.
2. Malenka RC , Bear MF ( 2004 ) LTP and LTD: an embarrassment of riches . Neuron 44 : 5 - 21 . doi:10.1016/j.neuron. 2004 .09.012.
3. Mozzachiodi R , Byrne JH ( 2010 ) More than synaptic plasticity: role of nonsynaptic plasticity in learning and memory . Trends in neurosciences 33: 17 - 26 . doi:10.1016/j.tins. 2009 .10.001.
4. Sjostrom PJ , Rancz E , Roth A , Hausser M ( 2008 ) Dendritic Excitability and Synaptic Plasticity . Biomedical Research: 769 - 840 . doi:10.1152/physrev. 00016. 2007 .
5. Wei DS , Mei Y a, Bagal a, Kao JP , Thompson SM , et al. ( 2001 ) Compartmentalized and binary behavior of terminal dendrites in hippocampal pyramidal neurons . Science (New York, NY) 293 : 2272 - 2275 . doi:10.1126/ science.1061198.
6. Debanne D , Poo MM ( 2010 ) Spike-timing dependent plasticity beyond synapse - pre- and post-synaptic plasticity of intrinsic neuronal excitability. Frontiers in synaptic neuroscience 2: 21 . doi:10.3389/fnsyn.2010.00021.
7. Li C , Lu J , Wu C , Duan S , Poo M ( 2004 ) Bidirectional modification of presynaptic neuronal excitability accompanying spike timing-dependent synaptic plasticity . Neuron 41 : 257 - 268 .
8. Losonczy A , Makara JK , Magee JC ( 2008 ) Compartmentalized dendritic plasticity and input feature storage in neurons . Nature 452 : 436 - 441 . doi:10.1038/nature06725.
9. Frick A , Magee J , Johnston D ( 2004 ) LTP is accompanied by an enhanced local excitability of pyramidal neuron dendrites . Nature neuroscience 7 : 126 - 135 . doi:10.1038/nn1178.
10. Hoffman DA , Magee JC , Colbert CM , Johnston D ( 1997 ) K+ channel regulation of signal propagation in dendrites of hippocampal pyramidal neurons . Nature 387 : 869 - 875 . doi:10.1038/43119.
11. Lei Z , Deng P , Xu ZC ( 2008 ) Regulation of Kv4.2 channels by glutamate in cultured hippocampal neurons . Journal of neurochemistry 106 : 182 - 192 . doi:10.1111/j.1471- 4159 . 2008 .05356.x.
12. Truchet B , Manrique C , Sreng L , Chaillan F a , Roman FS , et al. ( 2012 ) Kv4 potassium channels modulate hippocampal EPSP-spike potentiation and spatial memory in rats. Learning & memory (Cold Spring Harbor , NY) 19 : 282 - 293 . doi:10.1101/lm.025411.111.
13. Tsaur ML , Sheng M , Lowenstein DH , Jan YN , Jan LY ( 1992 ) Differential expression of K+ channel mRNAs in the rat brain and down-regulation in the hippocampus following seizures . Neuron 8 : 1055 - 1067 .
14. Castro P a , Cooper EC , Lowenstein DH , Baraban SC ( 2001 ) Hippocampal heterotopia lack functional Kv4.2 potassium channels in the methylazoxymethanol model of cortical malformations and epilepsy . The Journal of neuroscience: the official journal of the Society for Neuroscience 21 : 6626 - 6634 .
15. Bernard C , Anderson A , Becker A , Poolos NP , Beck H , et al. ( 2004 ) Acquired dendritic channelopathy in temporal lobe epilepsy . Science (New York, NY) 305 : 532 - 535 . doi:10.1126/science.1097065.
16. Chi XX , Xu ZC ( 2000 ) Differential Changes of Potassium Currents in CA1 Pyramidal Neurons After Transient Forebrain Ischemia Differential Changes of Potassium Currents in CA1 Pyramidal Neurons After Transient Forebrain Ischemia . Journal of neurophysiology 84 : 2834 - 2843 .
17. Zou B , Li Y , Deng P , Xu ZC ( 2005 ) Alterations of potassium currents in ischemia-vulnerable and ischemia-resistant neurons in the hippocampus after ischemia . Brain research 1033 : 78 - 89 . doi:10.1016/j.brainres. 2004 .11.023.
18. Lee HY , Ge W , Huang W , He Y , Wang GX , et al. ( 2012 ) Bidirectional Regulation of Dendritic Voltage-gated Potassium Channels by the Fragile X Mental Retardation Protein . Neuron 72 : 630 - 642 . doi:10.1016/j.neuron. 2011 .09.033. Bidirectional .
19. Gross C , Yao X , Pong DL , Jeromin A , Bassell GJ ( 2011 ) Fragile X mental retardation protein regulates protein expression and mRNA translation of the potassium channel Kv4 .2. The Journal of neuroscience: the official journal of the Society for Neuroscience 31 : 5693 - 5698 . doi:10.1523/JNEUROSCI.6661- 10 . 2011 .
20. Nagel G , Szellas T , Huhn W , Kateriya S , Adeishvili N , et al. ( 2003 ) Channelrhodopsin-2, a directly light-gated cation-selective membrane channel . Proceedings of the National Academy of Sciences of the United States of America 100 : 13940 - 13945 . doi:10.1073/pnas.1936192100.
21. Boyden ES , Zhang F , Bamberg E , Nagel G , Deisseroth K ( 2005 ) Millisecondtimescale, genetically targeted optical control of neural activity . Nature neuroscience 8 : 1263 - 1268 . doi:10.1038/nn1525.
22. Zhang F , Wang LP , Brauner M , Liewald JF , Kay K , et al. ( 2007 ) Multimodal fast optical interrogation of neural circuitry . Nature 446 : 633 - 639 . doi:10.1038/ nature05744.
23. Wang S , Szobota S , Wang Y , Volgraf M , Liu Z , et al. ( 2007 ) All optical interface for parallel, remote, and spatiotemporal control of neuronal activity . Nano letters 7 : 3859 - 3863 . doi:10.1021/nl072783t.
24. Schulz DJ ( 2006 ) Plasticity and stability in neuronal output via changes in intrinsic excitability: it's what's inside that counts . The Journal of experimental biology 209 : 4821 - 4827 . doi:10.1242/jeb.02567.
25. Kocsis E , Trus BL , Steer CJ , Bisher ME , Steven AC ( 1991 ) Image averaging of flexible fibrous macromolecules: the clathrin triskelion has an elastic proximal segment . Journal of structural biology 107 : 6 - 14 .
26. Wang S , Szobota S , Wang Y , Volgraf M , Liu Z , et al. ( 2007 ) All optical interface for parallel, remote, and spatiotemporal control of neuronal activity . Nano letters 7 : 3859 - 3863 . doi:10.1021/nl072783t.
27. Turrigiano G ( 2011 ) Too Many Cooks? Intrinsic and Synaptic Homeostatic Mechanisms in Cortical Circuit Refinement . Annual review of neuroscience 34 : 89 - 103 . doi:10.1146/annurev-neuro- 060909 - 153238 .
28. Birnbaum SG , Varga AW , Yuan LL , Anderson AE , Sweatt JD , et al. ( 2004 ) Structure and function of Kv4-family transient potassium channels . Physiological reviews 84 : 803 - 833 . doi:10.1152/physrev.00039. 2003 .
29. Yuan LL , Chen X ( 2006 ) Diversity of potassium channels in neuronal dendrites . Progress in neurobiology 78: 374 - 389 . doi:10.1016/j.pneurobio. 2006 .03.003.
30. Escoubas P , Diochot S , Celerier ML , Nakajima T , Lazdunski M ( 2002 ) Novel tarantula toxins for subtypes of voltage-dependent potassium channels in the Kv2 and Kv4 subfamilies . Molecular pharmacology 62 : 48 - 57 .
31. Zarayskiy VV , Balasubramanian G , Bondarenko VE , Morales MJ ( 2005 ) Heteropoda toxin 2 is a gating modifier toxin specific for voltage-gated K+ channels of the Kv4 family . Toxicon: official journal of the International Society on Toxinology 45 : 431 - 442 . doi:10.1016/j.toxicon. 2004 .11.015.
32. Stuart G , Spruston N , Sakmann B , Hausser M ( 1997 ) Action potential initiation and backpropagation in neurons of the mammalian CNS . Trends in neurosciences 20: 125 - 131 .
33. Magee JC , Johnston D ( 1997 ) A Synaptically Controlled, Associative Signal for Hebbian Plasticity in Hippocampal Neurons. Science 275 : 209 - 213 . doi:10.1126/science.275.5297.209.
34. Impey S , Obrietan K , Storm DR ( 1999 ) Making new connections: role of ERK/ MAP kinase signaling in neuronal plasticity . Neuron 23 : 11 - 14 .
35. Ribeiro MJ , Schofield MG , Kemenes I , O'Shea M , Kemenes G , et al. (n.d.) Activation of MAPK is necessary for long-term memory consolidation following food-reward conditioning . Learning & memory (Cold Spring Harbor , NY) 12 : 538 - 545 . doi:10.1101/lm.8305.
36. Sharma SK , Carew TJ ( 2004 ) The roles of MAPK cascades in synaptic plasticity and memory in Aplysia: facilitatory effects and inhibitory constraints. Learning & memory (Cold Spring Harbor , NY) 11 : 373 - 378 . doi:10.1101/lm.81104.
37. Rosenkranz JA , Frick A , Johnston D ( 2009 ) Kinase-dependent modification of dendritic excitability after long-term potentiation . The Journal of physiology 587 : 115 - 125 . doi:10.1113/jphysiol.2008.158816.
38. Varga AW , Yuan LL , Anderson AE , Schrader L a , Wu GY , et al. ( 2004 ) Calcium-calmodulin-dependent kinase II modulates Kv4.2 channel expression and upregulates neuronal A-type potassium currents . The Journal of neuroscience: the official journal of the Society for Neuroscience 24 : 3643 - 3654 . doi:10.1523/JNEUROSCI.0154- 04 . 2004 .
39. Nestor MW , Hoffman DA ( 2011 ) Differential cycling rates of Kv4.2 channels in proximal and distal dendrites of hippocampal CA1 pyramidal neurons . Hippocampus 000 . doi:10.1002/hipo.20899.
40. Ruiz-Gomez A , Mellstrom B , Tornero D , Morato E , Savignac M , et al. ( 2007 ) G protein-coupled receptor kinase 2-mediated phosphorylation of downstream regulatory element antagonist modulator regulates membrane trafficking of Kv4.2 potassium channel . The Journal of biological chemistry 282 : 1205 - 1215 . doi:10.1074/jbc.M607166200.
41. Dan Y , Poo MM ( 2006 ) Spike timing-dependent plasticity: from synapse to perception . Physiological reviews 86 : 1033 - 1048 . doi:10.1152/physrev. 00030. 2005 .
42. Karmarkar UR , Buonomano DV ( 2002 ) A Model of Spike-Timing Dependent Plasticity: One or Two Coincidence Detectors? A Model of Spike-Timing Dependent Plasticity: One or Two Coincidence Detectors ?: 507 - 513 .
43. Niehusmann P , Seifert G , Clark K , Atas HC , Herpfer I , et al. ( 2010 ) Coincidence detection and stress modulation of spike time-dependent long-term depression in the hippocampus . The Journal of neuroscience: the official journal of the Society for Neuroscience 30 : 6225 - 6235 . doi:10.1523/JNEUROSCI. 6411- 09 . 2010 .
44. Thomas GM , Huganir RL ( 2004 ) MAPK cascade signalling and synaptic plasticity . Nature reviews Neuroscience 5 : 173 - 183 . doi:10.1038/nrn1346.
45. Giovannini MG , Blitzer RD , Wong T , Asoma K , Tsokas P , et al. ( 2001 ) Mitogen-activated protein kinase regulates early phosphorylation and delayed expression of Ca2+/calmodulin-dependent protein kinase II in long-term potentiation . The Journal of neuroscience: the official journal of the Society for Neuroscience 21 : 7053 - 7062 .
46. Kelleher RJ , Govindarajan A , Jung HY , Kang H , Tonegawa S ( 2004 ) Translational control by MAPK signaling in long-term synaptic plasticity and memory . Cell 116 : 467 - 479 .
47. Watanabe S , Hoffman DA , Migliore M , Johnston D ( 2002 ) Dendritic K + channels contribute to spike-timing dependent long-term potentiation in hippocampal pyramidal neurons . Proceedings of the National Academy of Sciences of the United States of America 99 : 8366 - 8371 . doi:10.1073/ pnas.122210599.
48. Isaac JTR , Buchanan KA , Muller RU , Mellor JR ( 2009 ) Hippocampal place cell firing patterns can induce long-term synaptic plasticity in vitro . The Journal of neuroscience: the official journal of the Society for Neuroscience 29 : 6840 - 6850 . doi:10.1523/JNEUROSCI.0731- 09 . 2009 .
49. Zhao C , Wang L , Netoff T , Yuan LL ( 2011 ) Dendritic mechanisms controlling the threshold and timing requirement of synaptic plasticity . Hippocampus 21 : 288 - 297 . doi:10.1002/hipo.20748.
50. Andrasfalvy BK , Makara JK , Johnston D , Magee JC ( 2008 ) Altered synaptic and non-synaptic properties of CA1 pyramidal neurons in Kv4.2 knockout mice . The Journal of physiology 586 : 3881 - 3892 . doi:10.1113/jphysiol.2008.154336.
51. Chen X , Yuan LL , Zhao C , Birnbaum SG , Frick A , et al. ( 2006 ) Deletion of Kv4.2 gene eliminates dendritic A-type K+ current and enhances induction of long-term potentiation in hippocampal CA1 pyramidal neurons . The Journal of neuroscience: the official journal of the Society for Neuroscience 26 : 12143 - 12151 . doi:10.1523/JNEUROSCI.2667- 06 . 2006 .
52. Legenstein R , Maass W ( 2011 ) Branch-Specific Plasticity Enables SelfOrganization of Nonlinear Computation in Single Neurons . Journal of Neuroscience 31 : 10787 - 10802 . doi:10.1523/JNEUROSCI.5684- 10 . 2011 .
53. Gollo LL , Kinouchi O , Copelli M ( 2009 ) Active dendrites enhance neuronal dynamic range . PLoS computational biology 5: e1000402. doi:10.1371/ journal.pcbi.1000402.