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The Journal of Neurophysiology Vol. 88 No. 1 July 2002, pp. 249-255
Copyright ©2002 by the American Physiological Society
Division of Neuroscience, John Curtin School of Medical Research, Australian National University, Canberra, ACT 0200, Australia
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Raymond, Clarke R. and Stephen J. Redman. Different Calcium Sources Are Narrowly Tuned to the Induction of Different Forms of LTP. J. Neurophysiol. 88: 249-255, 2002. The essential role of calcium in the induction of long-term potentiation (LTP) has been well established. In particular, calcium influx via the N-methyl-D-aspartate (NMDA) receptor (NMDAR) is important for LTP induction in many pathways. However, the specific roles of other calcium sources in hippocampal LTP are less clear. The aim of the present study was to determine the appropriate conditions and extent to which non-NMDAR Ca2+ sources contribute to the induction of different forms of LTP in area CA1 of hippocampal slices. Increasing numbers of theta-burst trains (1, 4, and 8 TBS) induced LTP of increasing magnitude and persistence. Inhibition of ryanodine receptors caused inhibition of weak LTP induced by 1 TBS, but had no effect on more robust forms of LTP. Inhibition of IP3 receptors inhibited moderate LTP induced by 4 TBS, but had no effect when 1 TBS or 8 TBS were used. Inhibition of L-type voltage-dependent Ca2+ channels inhibited strong LTP induced by 8 TBS, but had no effect on weaker forms of LTP. These results show that different Ca2+ sources have different thresholds for activation by TBS trains. Furthermore, each Ca2+ source appears to be tuned to the induction of a different form of LTP. Such tuning could reflect an important link between different LTP induction and maintenance mechanisms.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Activity-dependent changes in
synaptic efficacy such as long-term potentiation (LTP) are widely
believed to underlie learning and memory in the brain (Bliss and
Collingridge 1993
; Martin et al. 2000).
Repetition of high-frequency or patterned stimulation protocols can
induce LTP of increasing magnitude and persistence, which in general
has been classified as either early-, or late-LTP on the basis of
activation of particular biochemical pathways. An extension of this has
been proposed based on the finding of three distinct LTP decay time
constants in vivo (LTP1, 2, and 3) (Abraham and Otani
1991; Racine et al. 1983), and their reliance on
different protein synthesis mechanisms (Otani et al.
1989; Raymond et al. 2000). However, little
information is available regarding possible differences in the
induction mechanisms of these forms of LTP.
An essential requirement for LTP induction in most neuronal types is an
increase in postsynaptic [Ca2+]. In hippocampal
CA1 pyramidal cells, the importance of the
N-methyl-D-aspartate (NMDA) receptor (NMDAR) for
LTP induction has been well established (Bliss and Collingridge
1993). Furthermore, activation of voltage-dependent Ca2+ channels (VDCCs) is important for a
seemingly independent form of LTP induced by high-intensity tetanic
stimulation (Grover and Teyler 1990; Morgan and
Teyler 2001). However, the contribution and conditions under
which calcium derived from the internal Ca2+
stores is important for LTP induction in CA1 are less clear
(Rose and Konnerth 2001).
The endoplasmic reticulum (ER) constitutes a large and important source
of Ca2+ for various neuronal signaling processes
(Berridge 1998; Mattson et al. 2000).
Ca2+ release from the ER is mediated by two types
of receptors, the ryanodine (RyR) and inositol 1,4,5-trisphosphate
(IP3R) receptors. RyRs are activated by increases in cytosolic
Ca2+ and are predominantly responsible for the
phenomenon of Ca2+-induced
Ca2+ release (CICR) (Berridge
1998; Zucchi and Ronca-Testoni 1997). IP3Rs are
primarily activated by IP3 generated via activation of metabotropic
receptors linked to phospholipase C (PLC), although they are also
modulated by cytosolic Ca2+ (Berridge
1993, 1998; Simpson et al. 1995).
Both types of receptor are widely distributed in the brain, with
characteristic patterns in particular regions. In CA1, RyRs are present
throughout the neuron, including dendritic shafts and spines, whereas
IP3Rs are less predominant in spines but highly expressed in dendritic
shafts (Sharp et al. 1993).
There is some evidence that internal Ca2+ stores
play a role in LTP induction in the hippocampus. Depletion of ER
Ca2+ stores by inhibition of the
Ca2+-ATPase pump with thapsigargin has been shown
to inhibit LTP, but only under conditions of weak conditioning stimuli
(Behnisch and Reymann 1995; Harvey and
Collingridge 1992; Wang et al. 1996). Similarly,
targeting RyRs with ryanodine or dantrolene seems only to affect weak
LTP (Obenaus et al. 1989; Wang et al.
1996). However, very few pharmacological studies provide
specific information on the individual roles of RyRs and IP3Rs in LTP
induction in area CA1. Mutations of RyRs have produced conflicting
results (Balschun et al. 1999; Futatsugi et al.
1999; Shimuta et al. 2001), and surprisingly, a
study of IP3R knockout mice revealed facilitation of LTP induced by
very weak stimulation (Fujii et al. 2000).
We sought to investigate the roles of Ca2+ sources other than the NMDA receptor in LTP in hippocampal area CA1. Specifically, we have studied the effects of pharmacological agents on LTP induction across a range of stimulus protocols to determine the specific conditions under which each Ca2+ source is important for LTP induction.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Male Wistar rats (7-8 wk) were anesthetized with halothane and decapitated, and the brains were rapidly removed and submerged in ice-cold artificial cerebrospinal fluid (ACSF, containing, in mM, 124 NaCl, 3.2 KCl, 1.25 NaH2PO4, 26 NaHCO3, 2.5 CaCl2, 1.3 MgCl2, and 10 D-glucose, equilibrated with 95% O2-5% CO2). Hippocampii were dissected free, and area CA3 was removed by a manual cut to reduce potential hyperexcitability. Transverse hippocampal slices (400 µm) were prepared using a McIlwain tissue sectioner, transferred to a submersion brain slice chamber, and preincubated for at least 2 h in a continuous flow (2 ml/min) of ACSF at 32.5°C.
Extracellular synaptic potentials were recorded from stratum radiatum
in area CA1 using glass microelectrodes (2-5 M
) filled with 2 M
NaCl. Baseline synaptic responses were evoked by stimulation of the
Schaffer collateral/commissural pathway at 0.033 Hz (0.1-ms pulse-width) with a Teflon-insulated tungsten monopolar electrode. The
stimulation intensity was adjusted to elicit field excitatory postsynaptic potentials (fEPSPs) of approximately two-thirds maximum amplitude. LTP was induced by theta-burst stimulation (TBS), consisting of trains of 10 × 100-Hz bursts (5 pulses/burst) with a 200-ms interburst interval, at the test pulse intensity. One train of 10 bursts is denoted as 1 TBS. When multiple trains were delivered (i.e.,
4 TBS and 8 TBS) the intertrain interval was 30 s.
Maximum slopes of fEPSPs were measured off-line and expressed as percentage change from baseline, calculated as the average of the last 15 min of baseline recordings. LTP was measured as the average of the last 10 points in the recording period. Two-tailed Student's t-tests were performed to determine significance at the 95% confidence level, unless otherwise noted. Data are presented as group means ± SE. Drugs were bath applied via the perfusion medium. Xestospongin C and ryanodine were obtained from Calbiochem (San Diego, CA). Nifedipine was obtained from Sigma (Castle Hill, Australia).
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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LTP induced by 1, 4, and 8 theta-burst trains
Previous studies have shown that repetition of a particular
conditioning stimulus can induce LTP of increasing magnitude and persistence (Abraham and Huggett 1997; Bliss and
Gardner-Medwin 1973; Huang and Kandel 1994). We
sought to investigate potential differences in the relative importance
of calcium derived from different sources to the induction of LTP by 1, 4, and 8 trains of TBS. In control slices 1 TBS resulted in a
weak LTP that rapidly decayed to 4 ± 1% (mean ± SE) at
2 h post-TBS (n = 4, Fig.
1). For this reason, subsequent
experiments involving 1 TBS compare LTP at 1 h post-TBS, where
potentiation measured 22 ± 5% (n = 8).
Increasing the number of TBS trains to 4 resulted in a similar initial
level of potentiation, but a slower decay such that LTP measured
18 ± 1% 2 h post-TBS (n = 4, Fig. 1).
Finally, 8 TBS resulted in a large initial induction level and a robust
LTP measuring 32 ± 6% 2 h post-TBS (n = 6, Fig. 1). These results are similar to those obtained previously using
TBS in area CA1 in vitro (Abraham and Huggett 1997;
Cohen et al. 1998).
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To gain further insight on the differences in LTP induced by each
protocol, the post-TBS data for all slices in all control groups were
fit with a double exponential decay function, as described previously
(Raymond et al. 2000). Data from one slice in the
combined 8 TBS group was excluded because an acceptable fit could not
be made (
2 test, P < 0.0001). The rate constant of decay of the second, slower exponential
was then averaged for each TBS group and used as a measure of LTP
persistence. For clarity, the inverse of the mean rate constants for
each group were calculated to give the mean decay time constant (
),
expressed in minutes. The values obtained mirror the differences in
LTP magnitude: 1 TBS, 58 min (n = 4); 4 TBS, 110 min
(n = 8); 8 TBS, 230 min (n = 11). The relative differences in these values are consistent with the LTP 1/2/3
nomenclature (Abraham and Otani 1991; Raymond et
al. 2000).
Ryanodine receptors
First, we investigated the role of the ryanodine-sensitive calcium
stores in LTP induced by each of the TBS protocols. In these
experiments ryanodine (RY, 10 µM) was bath applied for 10 min prior
to, and during, the TBS trains, to inhibit CICR via RY receptors. LTP
induced by 1 TBS in the presence of RY was attenuated over the entire
time course post-TBS (Fig. 2,
A and B). At 1 h post-TBS, fEPSPs had
returned to baseline levels (2 ± 3%, n = 5) and
were significantly different from controls (22 ± 5%,
n = 8, P < 0.01). However, RY had no
significant effect on LTP induced by either 4 TBS or 8 TBS (Fig.
2B), with potentiation 2 h post-TBS measuring 24 ± 4% (n = 4; control, 18 ± 1%,
n = 4) and 32 ± 7% (n = 4;
control, 29 ± 5%, n = 6), respectively. RY had
no effect on normal synaptic transmission with the difference from
baseline fEPSP slope at 1 and 2 h postwash measuring 1 ± 2% and 
2 ± 1%, respectively (n = 4, Fig.
2A).
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Since LTP 1, 2, and 3 are defined on the basis of decay rates, the mean
time constants () for LTP induced in the presence of RY were
calculated and compared with the corresponding control values (Fig.
2C). In this and the following sections, statistical analysis was performed on the rate constant data prior to calculation of . RY caused a significant increase in the decay of 1 TBS LTP [ = 26 min, n = 5; control (1 h post-TBS
group), 69 min, n = 8, P < 0.05], but
had no effect on the decay of either 4 TBS LTP ( = 145 min,
n = 4; control, 110 min, n = 8) or 8 TBS LTP ( = 288 min, n = 4; control, 230 min,
n = 11). These results closely match the effects on LTP
magnitude and show that inhibition of RyRs prevents the induction of a
weak, rapidly decaying form of LTP.
IP3 receptors
Until recently, it has been difficult to directly investigate the
role of the IP3-sensitive calcium stores in LTP due to the lack of
specific pharmacological tools. We have taken advantage of a recently
characterized, selective, membrane permeable inhibitor, Xestospongin-C
(Xest-C) (Gafni et al. 1997), to test for the
involvement of IP3-mediated calcium release in LTP induction by each of
the three TBS protocols. LTP induced by 1 TBS was not affected by a
10-min application of 5 µM Xest-C (22 ± 6%, n = 4, 1 h post-TBS; control, 22 ± 5%, n = 8, Fig. 3B). Similarly, LTP
induced by 8 TBS was not significantly affected by Xest-C treatment
(29 ± 6%, n = 4, 2 h post-TBS; control,
29 ± 5%, n = 6, Fig. 3B). However, LTP induced by 4 TBS in the presence of Xest-C, decayed more rapidly than controls, and was significantly reduced at 2 h post-TBS
(6 ± 3%, n = 5; control, 18 ± 1%,
n = 4, P < 0.01, Fig. 3, A
and B). Xest-C had no significant effect on normal synaptic
transmission over the 2-h postwash recording period (4 ± 2%
2 h postwash, n = 3, Fig. 3A).
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Again, the values match the effects on LTP magnitude (Fig.
3C). Data from one slice in the 1 TBS + Xest-C group was
excluded because an acceptable fit could not be made
(2 test, P < 0.001). The
decay constants for 1 TBS LTP ( = 58 min, n = 3) and 8 TBS LTP ( = 208 min, n = 4) were
unaffected by Xest-C, whereas 4 TBS LTP decayed significantly faster
when induced in the presence of Xest-C ( = 53 min,
n = 5, P < 0.05). Together, these
results show that IP3Rs are important for the induction of LTP with
moderate magnitude and decay characteristics.
Voltage-dependent calcium channels
In addition to the internal calcium stores, calcium entry through
VDCCs could increase cytoplasmic calcium concentration during LTP
induction. Indeed, very high-frequency stimulation, or high-intensity theta-burst stimulation, have been shown to induce LTP that is dependent on VDCC activation (Grover and Tyler 1990;
Morgan and Teyler 2001). To test for the involvement of
L-type VDCCs in LTP induced by each of our TBS protocols, we applied 10 µM nifedipine for 10 min prior to, and during, conditioning
stimulation. As expected, nifedipine had no effect on LTP induced by 1 TBS (24 ± 3%, n = 5, 1 h post-TBS; control,
22 ± 5%, n = 8, Fig.
4B). Similarly, 4 TBS-induced
LTP was unaffected by nifedipine (20 ± 2%, n = 6, 2 h post-TBS; control, 24 ± 4%, n = 4, Fig. 4B). However, nifedipine caused a dramatic reduction in
LTP induced by 8 TBS across the entire post-TBS time course, with
potentiation measuring 10 ± 3% 2 h post-TBS
(n = 6; control, 32 ± 6%, n = 6, P < 0.01, Fig. 4, A and B).
Nifedipine had no significant effect on normal synaptic transmission
over the 2-h postwash recording period (6 ± 1% 2 h
postwash, n = 3, Fig. 4A).
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As before, analysis of decay time constants revealed a close
relationship between LTP magnitude and decay (Fig. 4C). The
presence of nifedipine during LTP induction had no effect on the decay of 1 TBS LTP ( = 76 min, n = 5) or 4 TBS LTP
( = 125 min, n = 6), but significantly enhanced
the decay of 8 TBS LTP ( = 65 min, n = 6, P < 0.05). These results show that L-type VDCCs
contribute only to the induction of a robust, slowly decaying form of LTP.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The results of our experiments are summarized in Fig. 5A, where the effect of each inhibitor is shown as the percentage inhibition of the control LTP across the three TBS protocols. Thus Fig. 5A illustrates the apparent degree of involvement of ryanodine receptors, IP3 receptors, and VDCCs at each level of LTP.
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Thresholds for activation of different calcium sources
An important observation from Fig. 5A is that different
calcium sources appear to be activated in sequence, according to
particular threshold levels of synaptic activity produced by the TBS
protocol. RyRs appear to have the lowest activation threshold,
consistent with previous findings that RyRs are involved in LTP induced
by very weak stimulation protocols (Behnisch and Reymann
1995; Harvey and Collingridge 1992;
Obenaus et al. 1989). The sensitivity of RyRs to weak
synaptic activity is also supported by the finding that single synaptic
events can evoke ryanodine-sensitive calcium transients in hippocampal
organotypic cultures (Emptage et al. 1999; but see
Yuste et al. 1999). In cultures, the RyRs were activated by Ca2+ entering via the NMDA receptor. This is
also the most likely mechanism for RyR activation in the present
experiments, suggesting that, although NMDA receptor activation is
often necessary for LTP induction (Bliss and Collingridge
1993), the Ca2+ signal is not necessarily
sufficient and may be amplified by CICR during low level stimulation.
The present experiments constitute the first direct comparison of the
roles of RyRs and IP3Rs in LTP induction. An important finding was that
IP3Rs become effective in LTP induced by a higher number of stimulus
repetitions than RyRs. Activation of IP3Rs is complicated by the
dual-agonist role played by IP3 and cytosolic Ca2+ (Berridge 1993,
1998). The higher threshold for IP3Rs in LTP induction
could therefore be due to 1) a requirement for a high level,
or prolonged period of glutamate release to activate perisynaptically located mGluRs (Lujan et al. 1996; Scanziani et
al. 1997) and raise the IP3 concentration sufficiently, or
2) a requirement to raise cytosolic
Ca2+ to an optimal level for IP3 activation of
the receptors. Previous findings that group I mGluRs are important for
LTP induced by particular protocols provided indirect evidence of a
role for IP3Rs (Raymond et al. 2000; Wilsch et
al. 1998). Our findings confirm and extend previous results,
providing direct evidence of a requirement for IP3R activation only in
LTP of similar magnitude and persistence to that reported to be mGluR sensitive.
The finding that L-type VDCCs do not contribute significantly to LTP
until the highest number of stimulus repetitions are used is consistent
with the very high-frequency or high-intensity stimulation required to
induce VDCC-LTP (Grover and Teyler 1990; Morgan
and Teyler 2001). However, the question is raised why
repetition of TBS trains spaced at 30-s intervals should be an
effective stimulus for activating VDCCs, when a single train does not
appear to be? One explanation could be that during 8 TBS, early TBS
trains induce NMDA receptor-dependent LTP of
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) currents,
thereby allowing subsequent trains to reach the threshold for VDCC
activation (Morgan and Teyler 2001). Alternatively, some
aspect of preceding trains could "prime" VDCCs for activation by
subsequent trains (i.e., metaplasticity) (see Abraham and Tate 1997).
Tuning of calcium sources to different levels of LTP
A second notable feature of the data illustrated in Fig. 5A is that each calcium source is important only within a relatively narrow range of stimulus trains. Thus, as well as having different activation thresholds, the importance of each Ca2+ source in LTP induction diminishes as the number of TBS trains increases beyond a preferred level. One explanation for this phenomenon is that calcium sources may remain active, but their relative contributions to LTP may become redundant as the number of TBS trains increases and other sources become active (Fig. 5B). Alternatively, as the threshold for one Ca2+ source is reached, sources with lower activation thresholds may be inhibited (Fig. 5C).
In the scenario outlined in Fig. 5B, some characteristic of
the Ca2+ signal (e.g., magnitude or time
integral) from each source is the major determinant of the level of LTP
induced. This type of scenario has been proposed to explain how
Ca2+ acts as the induction signal for both LTP
and long-term depression (LTD), with LTD induced by a "weaker"
Ca2+ signal than LTP (Artola and Singer
1993; Lisman 1994). In the present case, calcium
sources with higher activation thresholds, once activated, could
contribute relatively more to the overall signal, thereby reducing the
importance of ongoing signals from more easily activated sources. In
the alternative scenario (Fig. 5C), each source contributes
similar levels of Ca2+, but is closely associated
with a unique effector system underlying a particular form of LTP. The
apparent lack of involvement of RyRs and then IP3Rs with successive TBS
trains may reflect inhibition of these receptors with increasing
stimulation. Both types of receptor display bell-shaped
calcium-response curves (Bezprozvanny et al. 1991;
Finch et al. 1991), that could underlie our observations if Ca2+ concentrations increased appropriately
during repetitive TBS trains.
It should be noted that these models do not make any assumptions about
whether the various calcium sources are contributing to NMDAR-dependent
or -independent forms of LTP. In fact, the present results suggest that
the NMDA/non-NMDA nomenclature may be misleading and that rather there
may be several LTP types, each associated with its own specific
induction-maintenance pathway. Interestingly, inhibition of non-NMDA
calcium sources during LTP induction can interfere with persistence
without effect on the initial level of potentiation (see Fig. 3). These
findings are consistent with the idea that that non-NMDA calcium
sources are more important for the induction of long-term
potentiation per se, and that NMDAR activation alone may only induce
STP or very weak LTP (Borroni et al. 2000;
Cavus and Teyler 1996; Morgan and Teyler
2001). Nonetheless, the models presented here deal with the
coding mechanism that links non-NMDA calcium signals to different levels of LTP, and their usefulness in this regard is not affected by
the role of the NMDA receptor in LTP.
Linking LTP induction and maintenance
In either scenario outlined above, an important implication is
that each Ca2+ source appears to be uniquely
associated with LTP of particular magnitude and persistence. Thus it
may now be possible to classify LTP according to induction
mechanisms as well as maintenance mechanisms. Under current
classification, LTP is defined on the basis of maintenance. Early-LTP
(or LTP1) is short lasting and involves posttranslational modification
of proteins (Malenka et al. 1989; Malinow et al. 1988). Late-LTP (or LTP2/3) is of greater magnitude and
persistence and requires activation of protein synthesis pathways
(Abraham and Otani 1991; Krug et al.
1984; Nguyen et al. 1994; Raymond et al.
2000). In the present results, there is a visible correlation between the LTP associated with RyRs, IP3Rs, and VDCCs and LTP 1, 2, and 3 as described in vitro. It is possible, therefore that during LTP
induction, each Ca2+ source is tuned to activate
its own specific LTP maintenance mechanism, whether by virtue of the
characteristics of the Ca2+ signal, or the
association of Ca2+ channels and effectors in
discrete microdomains. This has the effect of blurring the traditional
distinction between LTP induction, expression, and maintenance, and
invokes the concept of LTP type-specific intracellular pathways that
are selectively activated by particular patterns of afferent activity.
RyRs are prominent in dendritic spines of CA1 pyramidal neurons,
whereas IP3Rs are virtually absent from these structures. On the other
hand, IP3Rs are highly expressed in the dendritic shafts of CA1
pyramidal neurons, whereas RyRs are less prominent and are mostly
observed in patches immediately adjacent to spines (Sharp et al.
1993). These expression patterns could provide sufficient compartmentalization to enable differentiation between RyR- and IP3R-mediated signals in these neurons. The presence of RyRs in spines
may give them unique access for activating kinases associated with the
postsynaptic density that might underlie LTP1 (e.g., CaMKII)
(Lisman and Zhabotinsky 2001). In dendritic shafts,
IP3Rs may be well placed to activate the mGluR-dependent, local protein synthesis underlying LTP2 (Raymond et al. 2000). In area
CA1, L-type VDCCs are predominantly located on the soma and proximal dendrites (Hell et al. 1996; Magee and Johnston
1995; Westenbroek et al. 1990), and their
blockade prevents both late-LTP and associated increases in
CRE-mediated gene expression (Impey et al. 1996). Furthermore, behavioral studies suggest that LTP induced by VDCC activation during hippocampal-dependent learning is important for
long-term memory (Borroni et al. 2000).
In conclusion, although activation of NMDA receptors is known to be important for LTP induction in area CA1, our results show that other Ca2+ sources make an important contribution. Ryanodine receptors, IP3 receptors, and voltage-dependent calcium channels appear to have different thresholds for activation by LTP-inducing stimuli. Furthermore, selective activation of RyRs, IP3Rs, or VDCCs by conditioning stimuli of different durations appears to enable induction of specific levels of LTP. Such "tuning" could reflect strong links between different Ca2+ sources and LTP maintenance processes, and provide a mechanism allowing particular patterns of afferent activity to selectively induce different phases of LTP.
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ACKNOWLEDGMENTS |
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We thank G. Rodda for assistance with graphics, and Drs. John Bekkers, Pankaj Sah, and Greg Stuart for valuable comments on earlier versions of the manuscript.
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FOOTNOTES |
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Address for reprint requests: C. R. Raymond, Division of Neuroscience, John Curtin School of Medical Research, GPO Box 334, Australian National University, Canberra, ACT 0200, Australia (E-mail: clarke.raymond{at}anu.edu.au).
Received 22 January 2002; accepted in final form 13 March 2002.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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