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Neurotransmitter receptor and time
dependence of the synaptic plasticity
disrupting actions of Alzheimer’s
disease Ab in vivo
rstb.royalsocietypublishing.org
Igor Klyubin1,†, Tomas Ondrejcak1,†, Jennifer Hayes1, William K. Cullen1,
Alexandra J. Mably2, Dominic M. Walsh2 and Michael J. Rowan1
1
Research
Cite this article: Klyubin I, Ondrejcak T, Hayes
J, Cullen WK, Mably AJ, Walsh DM, Rowan MJ.
2014 Neurotransmitter receptor and time
dependence of the synaptic plasticity
disrupting actions of Alzheimer’s disease Ab
in vivo. Phil. Trans. R. Soc. B 369: 20130147.
http://dx.doi.org/10.1098/rstb.2013.0147
One contribution of 35 to a Discussion Meeting
Issue ‘Synaptic plasticity in health and disease’.
Subject Areas:
neuroscience, physiology
Keywords:
amyloid-b protein, long-term potentiation,
NMDA receptor, nicotinic receptor,
muscarinic receptor, Alzheimer’s disease
Author for correspondence:
Michael J. Rowan
e-mail: [email protected]
†
These authors contributed equally to this
study.
Department of Pharmacology and Therapeutics, Institute of Neuroscience, Trinity College, Biotechnology
Building, Dublin 2, Republic of Ireland
2
Laboratory for Neurodegenerative Research, Center for Neurologic Diseases, Brigham and Women’s Hospital,
Harvard Institute of Medicine, 77-Avenue Louis Pasteur, Boston, MA 02115, USA
Many endogenous factors influence the time course and extent of the
detrimental effects of amyloid b-protein (Ab) on synaptic function. Here, we
assessed the impact of varying endogenous glutamatergic and cholinergic
transmission by pharmacological means on the disruption of plasticity at
hippocampal CA3-to-CA1 synapses in the anaesthetized rat. NMDA receptors
(NMDARs) are considered critical in mediating Ab-induced inhibition of longterm potentiation (LTP). However, intracerebroventricular injection of Ab1 – 42
inhibited not only NMDAR-dependent LTP but also voltage-activated Ca2þdependent LTP induced by strong conditioning stimulation during NMDAR
blockade. On the other hand, another form of NMDAR-independent synaptic
plasticity, endogenous acetylcholine-induced muscarinic receptor-dependent
long-term enhancement, was not hindered by Ab1 – 42. Interestingly, augmenting endogenous acetylcholine activation of nicotinic receptors prior to the
injection of Ab1 – 42 prevented the inhibition of NMDAR-dependent LTP,
whereas the same intervention when introduced after the infusion of Ab
was ineffective. We also examined the duration of action of Ab, including
water soluble Ab from Alzheimer’s disease (AD) brain. Remarkably, the
inhibition of LTP induction caused by a single injection of sodium dodecyl
sulfate-stable Ab dimer-containing AD brain extract persisted for at least a
week. These findings highlight the need to increase our understanding of
non-NMDAR mechanisms and of developing novel means of overcoming,
rather than just preventing, the deleterious synaptic actions of Ab.
1. Introduction
The last 10 years has seen little progress in the pharmacotherapy of Alzheimer’s
disease (AD), although there is a small number of ongoing promising clinical
trials, especially those focusing on treating patients at an early stage [1,2]. Current
approved pharmacotherapy is based on two main strategies. First, anticholinesterase drugs, which augment ongoing cholinergic transmission, thereby
activating both nicotinic and muscarinic acetylcholine receptors. Second, memantine, which is a weak NMDA-type glutamate receptor (NMDAR) channel
blocker, thereby preventing presumed inappropriate activation of these receptors.
Neither class of drug treatment is clinically very effective, with a subset of patients
obtaining modest benefit at best, over a relatively brief period [3]. Rather than
modifying the insidious progress of the disease the drugs are considered to act
as symptomatic treatments primarily targeting cognitive impairment.
There is a growing consensus, given the available data, that the amyloid
b-protein (Ab) ‘hypothesis’ of AD has reached ‘theory’ status [4]. Although
the neuropathological hallmark plaques are composed largely of fibrillar Ab,
most attention has been devoted to investigating the pathophysiological role
& 2013 The Author(s) Published by the Royal Society. All rights reserved.
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There are two related aspects to the involvement of NMDARs:
how does Ab affect NMDAR-independent forms of synaptic
plasticity, and what is the role of NMDAR-independent mechanisms in the disruptive actions of Ab? Some years ago, we
reported that, in vitro, NMDAR-independent LTP was resistant
to inhibition by Ab1 – 42 [10]. Moreover, we found strong evidence that the inhibition of NMDAR-dependent LTP by Ab
is prevented by selective block of GluN2B subunit-containing
NMDARs in vivo [11], which was confirmed in vitro [12–14].
However, not all NMDAR-dependent LTP is susceptible to
inhibition by Ab, and Ab can facilitate NMDAR-independent
long-term depression [11,12,15].
In order to compare the effect of Ab on NMDAR-dependent and -independent forms of LTP in vivo, we have used
two different high-frequency conditioning stimulation (HFS)
protocols. Our standard HFS at 200 Hz triggers robust LTP
that is completely blocked by injection of different NMDAR
antagonists, including D-AP5 [16,17]. By contrast, i.c.v. injection of D-AP5 fails to fully block LTP induced by repeated
strong HFS at 400 Hz [17]. The additional, D-AP5 resistant,
LTP is fully inhibited by the R- and T-type voltage-activated
Ca2þ channel blocker mibefradil [17 –20]. We found that both
forms of LTP were strongly inhibited by Ab1 – 42 in vivo. Thus,
after the i.c.v. injection of Ab1 – 42, the standard HFS induced
a decremental LTP that decayed back to baseline over a 2–3 h
period (figure 1a). The same dose of Ab1 – 42 completely inhibited all phases of LTP induced by the strong HFS protocol
applied in the presence of D-AP5 (figure 1b).
The strong inhibition of NMDAR-independent LTP in the
same pathway in D-AP5-injected rats in vivo was surprising.
Previously, as noted above, we reported that NMDARindependent LTP induced by strong HFS in the presence of
D-AP5 in the same pathway was resistant to inhibition in
rat hippocampal slices [10]. One likely explanation for the
apparent discrepancy is that the mechanisms of NMDARindependent LTP induced by strong HFS are different
in vivo and in vitro. Indeed, strong HFS-induced NMDARindependent LTP in vitro is known to require Ca2þ entry
through dihydropyridine-sensitive L-type voltage-activated
channels [21] rather than R-/T-type channels as found here
3. Endogenous acetylcholine-dependent
mechanisms
Anticholinesterase drugs increase the magnitude and time
course of cholinergic transmission via activation of either
muscarinic or nicotinic receptors. In the absence of Ab, these
agents have been found to enhance LTP, for example by lowering the induction threshold [8]. Indeed, Gu & Yakel [29]
recently reported that pairing of electrically evoked release of
acetylcholine (ACh) and stimulation of excitatory synaptic
transmission in the Schaffer-collateral/commissural pathway
induced LTP that was mediated through either muscarinic
or nicotinic receptors, depending on the temporal sequence.
Nicotinic receptor-dependent LTP was mediated through
a7-receptor facilitation of Ca2þ entry through NMDARs on
dentritic spines. Muscarinic receptor-mediated LTP was
much less sensitive than nicotinic receptor-mediated LTP to
inhibition by Ab [29]. Somewhat similarly, in the medial perforant pathway of the dentate gyrus, anticholinesterases and
nicotine activation of a7-receptors enabled the induction
of additional NMDAR-dependent LTP that has different
properties from LTP induced in the absence of cholinergic
enhancement [30–32]. However, nicotinic receptor-dependent
LTP was resistant to inhibition in this pathway in vitro [33].
(a) Resistance of muscarinic-dependent long-term
synaptic enhancement to interference by Ab
We investigated the effects of Ab on muscarinic receptormediated synaptic plasticity in vivo using a well-characterized
pharmacologically induced persistent enhancement of transmission at CA3-to-CA1 synapses in anaesthetized rats [34,35].
By blocking cholinergic autoreceptors, the M2-selective antagonist methoctramine disinhibits the release of ACh, which,
in turn, activates M1/M5 receptors to trigger a long-term
2
Phil. Trans. R. Soc. B 369: 20130147
2. Ab-mediated disruption of NMDARdependent and -independent forms of
long-term potentiation
in vivo. Although the relatively strong inhibition of
NMDAR-independent LTP may be due to its relatively
small magnitude, an alternative explanation is that Ab interferes with the function of voltage-activated Ca2þ channels
[22,23]. Ab can boost Ni2þ-sensitive Ca2þ channels in hippocampal pyramidal cells [24,25], which could lead to excessive
or inappropriate Ca2þ entry into the cell. On the other hand,
Ab did not inhibit the function of Ni2þ-sensitive Ca2þ channels under the same in vitro conditions in which it inhibited
hippocampal NMDAR-dependent LTP [26]. Interestingly,
R-type channels appear to be important in mediating a
slow afterdepolarization that regulates hippocampal LTP
induction by certain firing patterns [27,28]. It will be important in future studies to determine whether Ab directly
affects the function of R- or T-type channels.
Our finding that both voltage-activated Ca2þ channel and
NMDAR-dependent LTP in vivo are strongly inhibited by
Ab indicates that the inhibitory action of Ab is independent
of the initial source of Ca2þ entry that triggers LTP. Furthermore, the ability of Ab to inhibit LTP in the presence of
D-AP5 indicates that NMDARs are not involved in the
disruption of certain forms of synaptic plasticity. This contrasts with the necessity for GluN2B subunit-containing
NMDARs in the inhibition of NMDAR-dependent LTP in
the same pathway under similar experimental conditions,
as reported by us previously [11].
rstb.royalsocietypublishing.org
of non-fibrillar, water-soluble forms of Ab [5,6]. Considerable
progress has been achieved in elucidating the disruptive
actions of soluble Ab on synaptic transmission and plasticity
of that transmission [7–9]. Extensive studies have examined
how endogenous factors influence the time course and extent
of the disruption of synaptic plasticity by soluble Ab, with
particular emphasis on the actions of putative ‘synaptotoxic’
assemblies ranging from small oligomers to relatively large
protofibrils. Here, we focus on the role of NMDARs and
cholinergic mechanisms in dysregulation of hippocampal
synaptic plasticity caused by acute administration of Ab
in vivo. We found evidence that extends or differs from previously reported in vitro findings. We also address a topic
that has potentially important clinical ramifications: the reversibility, be it spontaneous or intervention-based, of the synaptic
plasticity disruptive effects of Ab.
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Figure 2. Endogenous ACh-mediated, muscarinic receptor-dependent, synaptic
long-term enhancement was not inhibited by Ab in vivo. Injection of the selective M2 muscarinic receptor antagonist methoctramine (Meth, asterisk (*),
34 nmol, 5 ml, i.c.v.) triggered a rapid onset (less than 8 min) and persistent
(more than 2 h) enhancement of synaptic transmission (120.3 + 3.3% baseline
at 2 h post-Meth, n ¼ 5; p , 0.05 compared with pre-Meth baseline) in
vehicle-injected (hash (#), 5 ml i.c.v.) animals in the CA1 area of anaesthetized
rats. Similarly, in animals pre-injected with Ab1 – 42 (15 pmol), methoctramine
triggered a robust enhancement of transmission (132.1 + 9.9%, n ¼ 5,
p . 0.05 compared with vehicle). Insets show traces of the field EPSPs recorded
at times indicated. Horizontal bar, 5 ms; vertical bar, 1 mV; filled circles,
vehicle þ Meth; open circles, Ab þ Meth.
120
Figure 1. Ab1 – 42 inhibits both NMDAR-dependent and -independent forms of
LTP at CA3-to-CA1 synapses in the rat in vivo. (a) Whereas in vehicle-injected rats
(asterisk (*), 5 ml i.c.v.), the application of our standard, 200 Hz, conditioning
stimulation protocol (arrow) induced robust LTP that persisted for more than
3 h (161.2 + 7.6% at 3 h post-HFS, n ¼ 5; p , 0.05 compared with preHFS baseline, paired t-test), in animals injected with Ab1 – 42 (asterisk,
10 pmol, a dose that did not affect baseline transmission, not shown) LTP decayed
back to baseline levels during this period (100.2 + 3.4%, n ¼ 6; p . 0.05 compared with baseline, p , 0.05 compared with vehicle, paired and unpaired ttests, respectively). (b) In animals pre-injected with the NMDAR antagonist DAP5 (hash (#), 100 nmol, i.c.v.) strong, repeated 400 Hz conditioning stimulation
triggered LTP (133.0 + 7.8% at 2 h post-HFS, n ¼ 4; p , 0.05 compared with
pre-HFS baseline) in vehicle-injected animals but not in animals that were treated
with Ab1 – 42 (10 pmol) (94.2 + 5.8%, n ¼ 4; p . 0.05 compared with preHFS baseline, p , 0.05 compared with vehicle). Values are the mean % preHFS baseline field excitatory postsynaptic potential (EPSP) amplitude +s.e.m.
Insets show EPSP traces at the time indicated. Horizontal bar, 10 ms; vertical
bar, 1 mV; open circles, vehicle; filled circles, Ab.
enhancement of excitatory synaptic transmission. Consistent
with our previous findings [34,35], this pharmacologically
induced persistent potentiation does not require activation of
NMDARs. The administration (i.c.v.) of methoctramine caused
a rapid onset and persistent enhancement of baseline synaptic
transmission (figure 2). However, pre-injection of a dose of
Ab 1.5 times that which strongly inhibited HFS-induced
NMDAR-dependent LTP (figure 1) did not significantly affect
the methoctramine-induced persistent synaptic potentiation.
Thus in vivo, rather similar to the in vitro situation [29],
muscarinic-dependent synaptic plasticity is relatively resistant
to interference by Ab. This is somewhat surprising in view of
the evidence that Ab can potently impair muscarinic receptormediated signalling, necessary for certain forms of synaptic
plasticity [36]. This pharmacologically induced muscarinic Ach
receptor-dependent long-term synaptic enhancement is believed
to be mediated through activation of protein kinase A (PKA) and
atypical protein kinase C [34]. As activation of PKA prevents Abmediated inhibition of NMDAR-dependent LTP [37–39], it is
possible that a similar mechanism may help to explain the resistance of muscarinic Ach receptor-dependent long-term synaptic
enhancement to inhibition. Interestingly, M1-selective agonists
and positive allosteric modulators are being investigated as
potential therapeutic interventions in AD [40].
(b) Prevention, but not reversal, of the plasticity
disrupting action of Ab by augmenting
endogenous ACh activation of nicotinic receptors
Pretreatment with anticholinesterase drugs has been found
to prevent the inhibition of LTP by Ab both in vitro and
in vivo [32,41] but the underlying mechanisms are uncertain.
Given the ability of anticholinesterases to enhance control
LTP, as outlined above, it might be expected that post-Ab
treatment should be as effective as pretreatment in ameliorating synaptic plasticity deficits. We therefore compared the
effectiveness of pre- and post-Ab treatment with donepezil
on the inhibition of LTP.
Consistent with our previous studies with the anticholinesterase physostigmine [41], systemic pretreatment with
donepezil at a dose that did not affect baseline synaptic
transmission (102+0.7% pre-injection baseline at 2.5 h
Phil. Trans. R. Soc. B 369: 20130147
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Figure 3. Endogenous ACh-mediated nicotinic receptor-dependent prevention
but not reversal of the inhibition of LTP by Ab. (a) Pretreatment with the acetylcholinesterase inhibitor donepezil, by augmenting cholinergic activation of
nicotinic receptors, prevented the inhibition of LTP by Ab. (i) Systemic treatment
(hash (#)) with the anticholinesterase donepezil (1 mg kg – 1, s.c.), followed by
vehicle injection i.c.v. (asterisk (*), 5 ml), did not significantly affect the magnitude of LTP (Don þ Veh, 127.7 + 5.3% at 3 h post-HFS, n ¼ 4; p . 0.05
compared with 131.4 + 2.8%, n ¼ 4, in animals that received a vehicle
injection i.c.v. at 290 min, Veh þ Veh, ANOVA). By contrast, injection of
water-soluble Ab1 – 42 (80 pmol, i.c.v.) after a systemic vehicle injection strongly
inhibited LTP (Veh þ Ab, 105.4 + 4.9%, n ¼ 4; p , 0.05 compared with
control). (ii) Pretreatment with the same dose of donepezil completely prevented
the inhibition of LTP by Ab (Don þ Ab, 139.0 + 5.0%, n ¼ 5; p , 0.05
compared with Ab alone, p . 0.05 compared with control). However,
donepezil no longer prevented the inhibition of LTP by Ab in animals preadministered with the general nicotinic receptor antagonist mecamylamine
(Mec þ Don þ Ab, 1 mg kg21, i.p.) or the more selective a7-nicotinic receptor antagonist MLA (MLA þ Don þ Ab, 11 nmol in 5 ml, i.c.v.) (100.4 + 2.2
and 105.9 + 2.3%, at 2150 and 2130 min, respectively, n ¼ 5 per group,
p , 0.05 compared with donepezil þ Ab, p . 0.05 compared with
vehicle þ Ab). (b) By contrast, treatment with donepezil after the administration of Ab did not prevent the inhibition of LTP (Ab þ Don, 104.7 +
4.9%, n ¼ 5; p . 0.05 compared with 101.5 + 3.8%, n ¼ 5, in animals
injected with Ab alone, Ab þ vehicle, p , 0.05 compared with 131.4 +
2.8%, n ¼ 4, in control animals, Veh þ Veh). Insets show EPSP traces at
the time indicated. Horizontal bar, 10 ms; vertical bar, 2 mV.
Phil. Trans. R. Soc. B 369: 20130147
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post-injection, n ¼ 5, data not shown) or control LTP completely prevented the inhibition of LTP by i.c.v. injection of
Ab1 – 42 (figure 3a). We investigated the mechanism of this
ameliorative action of donepezil using nicotinic receptor antagonists. In animals pre-administered with the general nicotinic
receptor antagonist mecamylamine, at a dose that had no
obvious effect on control LTP (123.6 + 0.8% at 3 h post-HFS,
n ¼ 3, data not shown), treatment with donepezil no longer
prevented the inhibition of LTP by Ab. Likewise, pre-administration of the more a7-selective antagonist methyllycaconitine
(MLA) prevented the ameliorative effect of donepezil. Neither
mecamylamine nor MLA in combination with donepezil, at
the doses used in these studies, appeared to affect LTP
(127.0 + 1.9 and 131.3 + 8.5%, respectively, n ¼ 3 per group,
data not shown).
Next, we tested the ability of donepezil to ‘rescue’
Ab-mediated disruption of synaptic plasticity. When administered after the i.c.v. injection of Ab, at the same dose
level that was effective in the pretreatment protocol, donepezil did not abrogate the inhibition of LTP (figure 3b). As a
control, we determined that this schedule of donepezil treatment also did not affect LTP in the absence of Ab injection
(136.6 + 9.1 and 131.4 + 2.8% in donepezil or vehicle
groups, n ¼ 3 and 4, respectively, data not shown). We also
made sure that this dose of donepezil when given 1 h before
HFS-prevented LTP inhibition by Ab 30 min later (126.8 +
5.1 and 96.2 + 8%, donepezil þ Ab and vehicle þ Ab,
respectively, n ¼ 3 per group, data not shown).
These experiments provide strong evidence that endogenous ACh, via activation of nicotinic receptors, can prevent the
synaptic plasticity disrupting action of Ab in vivo.
The presumed involvement of a7-nicotinic receptors in
mediating the beneficial action of donepezil is consistent with
the ability of selective a7-nicotinic acetylcholine receptor
activators to enhance hippocampal LTP [42,43]. Indeed, their
high Ca2þ permeability [44] makes a7-nicotinic receptors
well suited to trigger intracellular Ca2þ-dependent signalling
pathways essential for the induction of LTP [45]. As noted
above, a7-nicotinic receptor activation can lower the threshold
for NMDAR-dependent LTP induction [29] or facilitate an
additional, Ab-resistant, NMDAR-dependent novel form of
LTP [33].
The apparent resistance of Ab-mediated inhibition of
LTP to ‘rescue’ by post-Ab treatment with donepezil in the
present studies may be due to the ability of Ab to block a7-nicotinic receptors [46]. Indeed Ab1 – 42 has a high affinity for these
receptors [47], and Ab1 – 42 potently inhibits a7-nicotinic receptor-mediated, NMDAR-dependent LTP in hippocampal slices
[29]. Resistance to anticholinesterase treatment given after the
infusion of Ab may help to explain the poor therapeutic efficacy when these agents are administered to many patients
with AD.
In contrast to the present findings, we and others previously
reported that selective activation of a7-nicotinic receptors via
exogenously applied agonist completely abrogated the inhibition
of LTP in hippocampal slices when administered after either
in vitro [48] or in vivo [43] exposure to Ab. However, when the
dose-dependence of the effect was examined in the ex vivo
study, the relative potency of the agonist was found to be reduced
several fold [43]. Future studies comparing the actions of more
selective nicotinic agonists or modulators in vivo will hopefully elucidate the apparent discordances and the potential
implications of these findings for future drug development.
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Figure 4. The synaptic plasticity disrupting action of Ab1 – 42 persists for several hours in acutely anaesthetized rats, whereas chronically implanted re-anaesthetized
rats develop tolerance to this action of Ab. (a,b) Injection of Ab1 – 42 (asterisk (*), 80 pmol i.c.v.) in acutely anaesthetized rats completely inhibited NMDARdependent LTP measured 3 h post-HFS when administered either (a) 30 min prior to HFS (arrow, standard 200 Hz protocol) (95.9 + 5.3%, n ¼ 5; p , 0.05 compared
with 129.5 + 4.5%, n ¼ 4, in vehicle-injected rats, unpaired t-test) or (b) 3 h prior to HFS (98.2 + 5.8%, n ¼ 6; p , 0.05 compared with 127.4 + 5.7%, n ¼ 5, in
vehicle-injected rats). (c) Although HFS induced similar magnitude LTP in chronically implanted re-anaesthetized rats (127.0 + 3.1%, n ¼ 5), injection of the same dose
of Ab1 – 42 now failed to significantly impair LTP (121.9 + 4.7%, n ¼ 5; p . 0.05 compared with vehicle, ANOVA). A dose four times higher (320 pmol) inhibited LTP
in the chronic animals (98.4 + 4.6%, n ¼ 7; p , 0.05 compared with vehicle). (d) Whereas the injection of either vehicle or 80 pmol Ab1 – 42 did not significantly
affect baseline transmission (n ¼ 5–6 per group), the higher dose of 320 pmol Ab1 – 42 caused a small but significant decrease in EPSP amplitude that was
similar in magnitude in both the acute and chronic preparations (87.5 + 5.1 and 89.4 + 3.0% pre-injection baseline at 3 h post-injection, n ¼ 6 and 7, respectively;
p , 0.05 compared with respective vehicle controls, p . 0.05 compared between acute and chronic, ANOVA). (i) Acutely anaesthetized rats, (ii) chronically implanted
re-anaesthetized rats. Insets show EPSP traces at the time indicated. Horizontal bar, 10 ms; vertical bar, 2 mV; open circles, vehicle; filled circles, Ab (80 pmol); filled
triangles, Ab (320 pmol).
4. Persistence of the synaptic plasticity
disrupting actions of soluble Ab
Because the deleterious effects of soluble Ab oligomers on
synaptic plasticity and plasticity-related mechanisms are
studied in hippocampal slices and anaesthetized animals,
most research has focused on their acute effects and how
these effects can be prevented by pretreatment with potential
therapeutic interventions. Little attention has been paid to
investigating the duration of action of acutely applied soluble
Ab on LTP. Consequently, much less is known about the
reversibility, either spontaneous or intervention-based, of
these disruptive effects. Indeed, Ab oligomers are not cleared
very efficiently from the brain compared with Ab monomers
[49], so there is a strong likelihood that the Ab oligomer
concentration in the brain decays relatively slowly with time.
Because the time window to study the duration of action of
Ab in the acutely anaesthetized rat is limited to a period of several hours, we also studied its effects in chronically implanted
animals. In the present experiments, initially we directly compared the ability of Ab to inhibit LTP when administered
30 min or 3 h before HFS in the acute preparation. We found
that the same dose that strongly inhibited LTP with 30 min pretreatment had a similar disruptive action when injected 3 h
prior to HFS (figure 4a,b).
We planned to examine the effects of Ab over a longer
time course in chronically implanted animals. We chose to
re-anaesthetize the animals when assessing the magnitude
of LTP in order to have a similar level of CNS arousal to
that present in the experiments on acutely anaesthetized animals [50]. To our surprise, the dose of Ab that strongly
inhibited LTP in the acute preparation failed to disrupt
LTP in chronically implanted re-anaesthetized animals
when injected 30 min before the HFS (figure 4c). We found
evidence that the threshold dose of Ab necessary to inhibit
LTP was raised. When four times the acute effective dose
was injected 30 min prior to the HFS in re-anaesthetized
animals, LTP was strongly inhibited. At this higher dose a
Phil. Trans. R. Soc. B 369: 20130147
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Figure 5. Water-soluble Ab in AD brain extract strongly and persistently inhibits LTP. (a) AD brain tris-buffered saline (TBS) extract (AD) was characterized by
immunoprecipitation and Western blot and found to contain approximately 5.06 ng ml21 Ab monomer (M) and approximately 2.7 ng ml21 SDS-stable dimer
(D). The concentration of soluble Ab in a TBS brain extract from a non-AD control (Con) was below the detection limit. (b) There was no significant difference
in baseline excitability between the controls and AD brain extract-treated animals as measured by (i) EPSP amplitude or (ii) stimulation intensity. (c) The acute
injection of AD brain extract (8 ml, i.c.v.) 15 min prior our standard 200 Hz HFS protocol (arrow) completely inhibited LTP measured 3 h post-HFS (105.4 + 3.8%,
n ¼ 5, p , 0.05, unpaired t-test, compared with 149.6 + 10.6% in Ab-immunodepleted AD brain extract, n ¼ 4, or vehicle-injected controls, n ¼ 3, combined
n ¼ 7) in urethane-anaesthetized rats. (d ) Similarly, a single injection (20 ml, i.c.v. under ketamine – xylazine anaesthesia) of Ab-containing AD brain TBS extract 7
days before HFS completely inhibited LTP (103.8 + 5.2%, n ¼ 5, p , 0.05, compared with 140.9 + 6.6% in Ab-immunodepleted AD brain extract, n ¼ 2, or
vehicle-injected controls, n ¼ 3, combined n ¼ 5) in urethane-anaesthetized rats. Insets show EPSP traces at the time indicated. Horizontal bar, 10 ms; vertical bar,
1 mV; open circles and bars, vehicle or Ab-immunodepleted AD brain extract; filled circles and bars, AD.
slow-onset, small reduction in baseline synaptic transmission
developed 2– 3 h after the injection (figure 4d ), which probably contributed partly to the apparent magnitude of LTP
inhibition in the chronically implanted rats. The higher
dose of Ab had a similar baseline depressant effect in the
acutely anaesthetized rats (figure 4d). These findings indicate
that relatively selective tolerance develops in chronically
implanted rats to the acute synaptic plasticity disrupting
action, but not the baseline depressant action, of Ab. Further
investigation will be needed to elucidate the mechanisms of
such selective tolerance and to determine whether similar
resistance to other acute effects of Ab develops in chronically
implanted animals.
Rather than determine the persistence of LTP inhibition in
animals chronically implanted with electrodes and a cannula,
which lowered the potency of Ab, we used a modified protocol. The duration of action of Ab after single injection using a
temporary cannula under recovery anaesthesia was assessed
a week later under non-recovery anaesthesia. For these experiments, we turned to studying the pathophysiologically most
relevant form of water-soluble Ab species and assemblies,
those present in AD brain. Soluble extracts of AD brain contain Ab monomers and sodium dodecyl sulfate (SDS)-stable
dimers at dramatically higher concentrations than in nonAD controls (figure 5a) [15,51]. Acute application of such
Ab-containing soluble extracts of AD brain rapidly and
potently inhibits LTP both in vitro [15,52] and in vivo [53,54].
Similar to what we reported previously, Ab-containing soluble extract of AD brain injected 15 min before HFS inhibited
LTP in urethane-anaesthetized rats (figure 5c). Remarkably,
we found that a single i.c.v. injection of the same AD brain
extract under recovery anaesthesia still inhibited LTP induction
when HFS was applied 7 days later under urethane anaesthesia
(figure 5d). Importantly, a single i.c.v. injection of an equivalent
volume of vehicle or the same soluble AD brain extract that had
been immunodepleted of Ab did not affect LTP when tested
immediately or 7 days later. There was no evidence for a
change in baseline synaptic transmission (figure 5b) or pairedpulse facilitation (1.83 + 0.05 and 1.79 + 0.09 facilitation ratio
at 40 ms interstimulus interval in controls and AD braininjected group, respectively, n ¼ 5 per group, data not shown).
Because we did not examine the acute effect of Ab injection
on LTP in animals that had a vehicle injection under recovery
anaesthesia a week previously, we do not know if the potency
of AD brain Ab was affected by the modified experimental protocol. Moreover, baseline properties of synaptic transmission in
other hippocampal pathways need to be investigated because
i.c.v. injection of similar AD brain extract in rats can cause ultrastructural changes, including reduced synaptic density, in the
stratum lacunosum moleculare of the CA1 region and outer
Phil. Trans. R. Soc. B 369: 20130147
(c)
EPSP (% baseline)
6
15
stimulus intensity (mA)
NS
EPSP amplitude (mV)
5
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Taken together, these findings indicate that non-NMDAR
mechanisms are important in regulating the deleterious
effects of Ab oligomers on synaptic plasticity and that once
initiated, reversing persistent disruption in vivo remains a
major challenge for the future.
6. Material and methods
(a) Animals and surgery
All experiments were carried out in accordance with guidelines
under licence from the Department of Health and Children, Ireland (86/609/EEC) using methods similar to those described
previously [58]. Male Wistar rats (250– 350 g) were anaesthetized
with urethane (1.5 g/kg, i.p.) and core body temperature was
maintained at 37.5 + 0.58C. A stainless steel guide cannula (22
gauge, 0.7-mm outer diameter, length 13 mm) was implanted
above the right lateral ventricle before the electrodes were
implanted ipsilaterally. Injections were made via a Hamilton
syringe which was connected to the internal cannula (28 gauge,
0.36 mm outer diameter). The injector was removed 1 min postinjection and a stainless steel plug was inserted. The position of
the cannula was verified postmortem by investigating the spread
of ink dye after i.c.v. injection. Teflon-coated tungsten wire (external
diameter 75 mm bipolar or 112 mm monopolar) electrodes were positioned in the stratum radiatum of area CA1. Screw electrodes located
over the contralateral cortex were used as reference and earth. The
stimulation and recording electrodes were optimally located using
a combination of physiological and stereotactic indicators.
In the case of chronically implanted animals, the insertion
of electrodes and cannula was carried out under recovery anaesthesia using a mixture of ketamine (80 mg kg – 1) and xylazine
(8 mg kg – 1) (both i.p.) as described above for acute experiments.
Rats were housed individually in their home cages with free
access to food and water and a 12 L : 12 D cycle for at least a
week postsurgery. Electrophysiological recordings were carried
out under urethane anaesthesia, as described above. To investigate the delayed effect of human brain extract, the injection
was carried out under recovery anaesthesia and the cannula
was then removed. The electrode implantation and recording
was carried out under urethane anaesthesia 7 days later.
(c) Chemicals
Stock solution (70 or 100 mM) of synthetic Ab1 – 42 (Bachem) was prepared in 0.1% ammonium hydroxide and stored at 2808C. To
produce soluble Ab, for the experiments illustrated in figures 3
and 4, the solution was centrifuged (100 000g at 48C for 3 h) [59]
and the upper 75% of the supernatant used. Donepezil hydrochloride (Aricept, purchased from St. James’s Hospital Pharmacy,
Dublin) was dissolved in water and injected s.c. (0.5 ml kg21). The
vehicle þ vehicle group in figure 3 received an i.c.v. injection of
vehicle 90 min before the HFS and the second injection (s.c.) either
30 min before or after the i.c.v. injection. Mecamylamine hydrochloride (Sigma) was dissolved in saline and injected i.p. (3 ml kg21).
D-AP5 (Tocris), methyllycaconitine citrate (Sigma) and methoctramine (Sigma) were dissolved in water for i.c.v. injection.
(d) AD brain extracts
AD brain extracts were prepared as described previously [55].
Human brain tissue was kindly provided by Matthew P. Frosch,
Massachusetts General Hospital and used in accordance with local
Ethics Committee guidelines. Samples of temporal cortex were
from an 83 year old female, who died with AD and Lewy body
dementia, and an 82 year old male control, who died free of neurodegeneration. Briefly, tris-buffered saline (TBS) extracts of cortex
were prepared by dounce homogenization and then clarified by
high-speed centrifugation. To eliminate bioactive small molecules
the supernatant was exchanged into ammonium acetate using a
5 ml Hi-trap de-salting column (GE Healthcare Bio-Sciences AB,
Uppsala, Sweden). One aliquot of the extract was immunodepleted
of Ab with the rabbit polyclonal anti-Ab antibody, AW8. Aliquots of
samples were stored at 2808C or used to assess Ab content with a
sensitive immunoprecipitation (IP)/western blotting (WB) procedure. AW8 was also used for IP and a combination of the antiAb40 and Ab42 monoclonal antibodies for WB. Ab concentration
was estimated by reference to known quantities of synthetic Ab1 – 42.
(e) Data analysis
The magnitude of potentiation is expressed as the percentage of
baseline during the initial 30-min period, expressed as mean + s.e.
of the mean, unless otherwise stated. For statistical analysis, EPSP
amplitudes were grouped into 10-min epochs. Standard one-way
ANOVA was used to compare the magnitude of LTP between
multiple groups followed by post hoc Tukey’s tests. Unpaired
Student’s t-tests were used for two-group comparisons. A value of
p , 0.05 was considered statistically significant.
Acknowledgements. We thank our colleague Prof. Roger Anwyl for the
continuous intellectual input provided. We also thank Dr Neil
Upton and Dr Robert Lai for helpful discussions. We thank Dr
P. Seubert and Dr D. Schenk (Elan Pharmaceuticals) for the generous
gift of 2G3 and 21F12.
Funding statement. This work was supported by grants from Science
(b) Electrophysiological recording
Test stimuli were delivered to the Schaffer-collateral/commissural
pathway every 30 s to evoke field excitatory postsynaptic potentials
(EPSPs) that were 45–60% maximum amplitude. With one
Foundation Ireland, the Health Research Board of Ireland and the
European Union Seventh Framework Programme 528 (Grant Agreement MEMOLOAD 201159) (M.J.R.), by the Health Research Board of
Ireland (I.K.) and by the Foundation for Neurologic Diseases
(D.M.W.).
7
Phil. Trans. R. Soc. B 369: 20130147
5. Conclusion
exception, LTP was induced using our standard 200 Hz protocol
of a single series of 10 trains of 20 stimuli with an intertrain interval
of 2 s. A repeated strong 400 Hz protocol (three sets of 10 trains of
20 pulses, intertrain interval of 2 s and interset interval of 5 min)
was used to investigate NMDAR-independent LTP [17]. The stimulation intensity was increased to 75% maximum during both
induction protocols. The magnitude of control LTP varied considerably over the period of carrying out these experiments. In order to
minimize the possible confounding effect of such variation in control LTP, the experiments in each study were interleaved.
rstb.royalsocietypublishing.org
molecular layer of the dentate gyrus when measured 2 days
later, after performing a passive avoidance learning task [55].
The persistence of the disruptive effect of Ab 7 days after a
single injection may be caused by residual Ab assemblies that
are poorly cleared from the brain. Alternatively, transient
exposure to Ab may trigger a cascade of events that persist
for long periods. For example, intracerebral injections of either
AD brain Ab or soluble Ab from amyloid precursor
proteintransgenic (APP) transgenic mouse brain have been
reported to act as seeds for the aggregation of endogenous
Ab in APP transgenic, but not wild-type, mice, several
months after innoculation [56,57]. It will be of interest to determine how much longer, beyond the week we report here, that
the synaptic plasticity disrupting action of soluble Ab from
AD brain persists in wild-type rats.
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