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Contents lists available at ScienceDirect

Biochemical Pharmacology
journal homepage: www.elsevier.com/locate/biochempharm

Review

The effect of a7 nicotinic receptor activation on glutamatergic

transmission in the hippocampus
Qing Cheng* , Jerrel L. Yakel
Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services,
Research Triangle Park, NC 27709, USA

A R T I C L E I N F O A B S T R A C T

Article history: Nicotinic acetylcholine receptors (nAChRs) are expressed widely in the CNS, and mediate both synaptic
Received 26 May 2015 and perisynaptic activities of endogenous cholinergic inputs and pharmacological actions of exogenous
Accepted 14 July 2015 compounds (e.g., nicotine and choline). Behavioral studies indicate that nicotine improves such cognitive
Available online xxx
functions as learning and memory, however the cellular mechanism of these actions remains elusive.
With help from newly developed biosensors and optogenetic tools, recent studies provide new insights
Keywords: on signaling mechanisms involved in the activation of nAChRs. Here we will review a7 nAChR’s action in
a7 Nicotinic acetylcholine receptor
the tri-synaptic pathway in the hippocampus. The effects of a7 nAChR activation via either exogenous
Glutamatergic transmission
Hippocampus
compounds or endogenous cholinergic innervation are detailed for spontaneous and evoked
Calcium glutamatergic synaptic transmission and synaptic plasticity, as well as the underlying signaling
cAMP mechanisms. In summary, a7 nAChRs trigger intracellular calcium rise and calcium-dependent signaling
pathways to enhance glutamate release and induce glutamatergic synaptic plasticity.
Published by Elsevier Inc.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. a7 nAChR properties and expression in the hippocampus . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. The effect of a7 nAChR’s activation by exogenous agonists .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. a7 Activation via cholinergic synapses in the hippocampus .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. Second messenger signaling upon activation of a7 nAChRs- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6. Significance and conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction prominent in the hippocampus, and has been linked with cognitive
deficits and a variety of neurological disorders and diseases, such
Nicotinic acetylcholine receptors (nAChRs) belong to the as Alzheimer’s diseases and schizophrenia [37,119,27,95,103].
superfamily of cys-loop cationic ligand-gated channels Schizophrenic patients are often heavy smokers [22], which has
[59,19,21,5]. They are activated by the endogenous ligand been suggested to be a form of self-medication to mitigate their
acetylcholine (ACh) and various exogenous ligands (e.g., nicotine cognitive dysfunctions [71]. The b-amyloid peptide (Ab1–42 or Ab
and choline) to exert their modulatory function on synaptic peptide), a pathological hallmark of Alzheimer’s disease, has been
excitability and plasticity [21,118,119]. The a7 nAChR subtype is shown to affect a7 nAChR’s function [113,74,91,66]. Moreover,
significant loss of a7 nAChR protein density was observed in the
hippocampus of both traumatic brain injury and prenatal restraint
Abbreviations: ACh, acetylcholine; DG, dentate gyrus; HFS, high frequency stress animal models [52,10]. Either activation of the a7 nAChR
stimulation; LTD, long-term depression; LTP, long-term potentiation; nAChR, with agonists, or potentiation with positive allosteric modulators
nicotinic ACh receptor; STP, short-term potentiation; PAM, positive allosteric (PAMs) (e.g., NS-1738), has been shown to improve hippocampal-
modulator. dependent learning and memory [13,109,117,14]. Conversely,
* Corresponding author.

http://dx.doi.org/10.1016/j.bcp.2015.07.015
0006-2952/ Published by Elsevier Inc.

Please cite this article in press as: Q. Cheng, J.L. Yakel, The effect of a7 nicotinic receptor activation on glutamatergic transmission in the
hippocampus, Biochem Pharmacol (2015), http://dx.doi.org/10.1016/j.bcp.2015.07.015
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genetic deletion and pharmacological inhibition of the a7 nAChR
in the hippocampus results in significant learning and memory
impairments [69,34,88,121,70], and worsens the learning and
memory deficits in a mouse model of Alzheimer’s disease [49].
Therefore, it is critical to understand the functional properties of
nAChRs in regulating hippocampal circuitry and synaptic plastici-
ty. Below, we will briefly review recent advances, with a particular
focus on a7 nAChRs (although a4b2 nAChRs also play an
important role), in the regulation of glutamatergic synaptic
transmission in the hippocampal formation.
2. a7 nAChR properties and expression in the hippocampus
The nAChRs are widely expressed throughout the brain in both
neurons and non-neuronal cells, and participate in a variety of
physiological functions [79,84,102]. In the mammalian brain, there
are six a (2–10) and three b (2–4) nAChR subunits, which have
been shown to form either hetero- or homopentameric nAChRs
[111,96,60,7,6]. The most prevalent nAChRs in the hippocampus are
comprised of a7 and a4b2 subtypes [59,7,5]. While a7 subunits
were initially thought to form mainly homopentameric a7
receptors, they have been shown to co-assemble with other
subunits to form functionally distinct native a7-containing
receptors [9,122,90,98,73,81,82]. Initially, we found that a7 and
b2 subunits co-assembled in vitro [64]; subsequently it was found
that basal forebrain cholinergic neurons express functional native
a7b2 receptors with an enhanced sensitivity to the amyloid-b
(Ab) peptide associated with AD [73]. Physiological studies have
shown that a7 nAChRs have lower affinity for acetylcholine, faster
desensitization kinetics, and higher calcium permeability than
a4b2 receptors [12,31,5]. Because of its high calcium permeability,
a7 nAChRs can function similar to NMDA receptors in the
modulation of synaptic plasticity.
In the hippocampal formation, distribution of mRNA for a7
nAChRs, as well as a-bungarotoxin (a-BTX) binding sites (which
label a7 nAChRs), are widespread throughout the dentate gyrus
(DG), CA3 and CA1 regions [107,29,3]. Functional a7 nAChR-
mediated currents have also been reported in CA3 and CA1
pyramidal neurons [57,45,46], mouse dentate granule cells [58]
and GABAergic interneurons [60]. Besides neuronal expression, a7
nAChRs are expressed on non-neuronal cells such as astrocytes in
the hippocampal CA1 region [102], which could play a role in
neuroprotection and inflammation [101]. Ultrastructural studies in
the CA1 region revealed immuno-gold particle labeling of a7
nAChRs at both pre- and postsynaptic compartments of both
GABAergic and glutamatergic synapses [29]. a7 nAChRs located on
presynaptic terminals can regulate release of other neurotrans-
mitters [59,19,21], while a7 nAChRs located on postsynaptic
membranes mediate cholinergic synaptic transmission. Taking
advantage of their high calcium permeability, functional a7
nAChRs can be mapped with sensitive calcium dyes and
genetically-encoded calcium indicators, which provide compli-
mentary information as to the locations of functional receptors
beyond the reach of traditional patch-clamp studies. The calcium
rise mediated by functional a7 nAChRs has been shown in
dendrites of CA1 [31] and CA3 pyramidal neurons [45], and dentate
granule cells at their mossy fiber terminals [15]. Optical recordings
revealed that the amplitude of the a7 nAChR-mediated calcium
response was significantly larger in the dendrites (than in the
soma) despite smaller a7 nAChR current responses [32], suggest-
ing that functional a7 nAChRs cluster differentially around
neuronal compartments [62]. With the aid of newly developed
a7 PAMs, we observed a7 nAChR-mediated calcium rise via
GCaMP3 imaging in giant mossy fiber terminals [15], which is
consistent with the study using the calcium dye Fura-2 [44]. In
addition, a7 nAChRs also distribute perisynaptically to mediate
Please cite this article in press as: Q. Cheng, J.L. Yakel, The effect of a7 nicotinic receptor activation on glutamatergic transmission in the
hippocampus, Biochem Pharmacol (2015), http://dx.doi.org/10.1016/j.bcp.2015.07.015
modulating effects of non-synaptically released ACh [61,21,5,101].
The density and distribution of a7 nAChRs changes markedly
during early development [2,1], and differs among different mouse
strains and species [94,4]. Moreover, genetic polymorphism of the
a7 nAChR gene (CHRNA7) linked to schizophrenia generated a
partially duplicated a7 nAChR (CHRFAMA7A, dupa7) subunit
either with or without a 2-bp deletion (CHRFAMA7A-D2bp,
dupDa7) [41,105], which could change the properties of the a7
nAChR and modify neuronal connections [104]. An in vitro study
showed that both dupa7 and dupDa7 co-assemble with the a7
subunit to form functional receptors with normal sensitivity to
ACh and lower sensitivity to choline, though the calcium
permeability of these mutated a7 receptors remains unclear [114].
3. The effect of a7 nAChR’s activation by exogenous agonists
Many groups have studied how a7 nAChR activation modulates
glutamatergic synaptic transmission with nicotine or selective
agonists to activate a7 nAChRs in the hippocampus. We will focus
mainly on the direct a7 nAChR-mediated effect on glutamatergic
synapses, and not the indirect impact derived from a7 nAChR
activation on GABAergic neurons, which also can modulate
synaptic plasticity in pyramidal cells.
For spontaneous glutamate release, acute nicotine application
increased the frequency of spontaneous miniature EPSCs from
dissociated hippocampal neurons [44,93], and CA1 [67] and CA3
pyramidal neurons [100]; this suggests a presynaptic location of
nicotine's action. The nicotine-induced frequency increase of
mEPSCs was blocked by MLA (an a7-selective antagonist) [44], and
absent in a7 knockout mice [67], suggesting that a7 nAChRs
mediated this enhancement. Moreover, a brief application of
nicotine converted presynaptically silent synapses into conductive
ones at immature Schaffer collateral-CA1 connections [76]. Besides
its modulatory effect on mEPSC frequency, activation of a7 nAChRs
could directly trigger glutamate release from mossy fiber terminals
[99]. The direct measurement of glutamate release from hippo-
campal synaptosomes showed significant release upon choline
application [123], which is consistent with electrophysiological
findings. In vivo extracellular recordings from CA3 pyramidal
neurons showed robust increases in firing induced by nicotine and
blocked by MLA; this was found to be due to enhanced glutamate
release [53]. The a7 nAChR’s effect on spontaneous glutamate
release occurred within seconds after agonist application and
lasted for several minutes after agonist removal, suggesting that
both immediate calcium rise through a7 nAChR activation and
longer-term calcium-dependent signaling cascades are involved.
For the evoked release of glutamate, a7 nAChR activation can
increase the amplitude of evoked EPSCs in cultured hippocampal
neurons [93], for CA3 to CA1 pyramidal neuron synapses, DG to
CA3 synapses, and perforant path to DG glutamate synapses
[106,89,15]. The increase in amplitude was associated with a
significant increase in the probability of release along with a
significant decrease of the PPR (paired-pulse ratio) [106]. Our
study [15] of CA3 pyramidal neurons showed that a7 nAChR
activation enhanced eEPSC amplitude, which persisted for 5–
10 min after the removal of agonist. Similar long-lasting effects of
nAChR agonists on neurotransmitter release were observed by
others as well [68,124]. Studies from both spontaneous and evoked
glutamatergic synaptic transmission showed that presynaptic a7
nAChRs mediated enhancement of glutamate release, suggesting
that a7 nAChRs could be activating the same calcium-dependent
signaling cascades to sustain the nicotinic enhancement of
glutamate release. In the prefrontal cortex, nicotine induced an
increase in frequency and amplitude of spontaneous EPSCs, but did
not affect the amplitude of evoked glutamatergic transmission
from layer II/III to layer V pyramidal neurons [17], suggesting that
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multiple calcium-dependent pathways could be involved in its
action.
Hippocampal LTP is a well-accepted cellular model for learning
and memory. The effect of a7 nAChR’s activation on synaptic
plasticity is dictated by the timing of its activation and electrical
stimulation on glutamatergic synaptic currents. When a7 nAChR
agonists were bath perfused, the activation of a7 nAChRs
facilitated the induction of LTP [54,39], and enhanced both early
and late LTP [65] in the CA1 hippocampal region. When a7 nAChRs
were activated via brief application of ACh, which coincided or
preceded (by 1–5 s) high frequency stimulation (HFS), this
produced LTP under mild presynaptic stimulation conditions at
CA1 pyramidal neurons [57]. Outside of these time frames, the
mismatch of nAChR activity and stimulation led to short-term
potentiation (STP) [42]. The a7 nAChR-mediated enhancement of
LTP was due to its ability to increase presynaptic release of
glutamate and postsynaptic depolarization. Activation of a7
nAChRs has also been shown to suppress LTD induction at CA3-
CA1 synapses [40,83]. In the DG, acute a7 nAChR activation
enhanced HFS-induced LTP, and a7 nAChR PAMs reduced the
threshold for LTP induction, an effect which required ERK and PKA
activity [116]. For mossy fiber LTP, a7 nAChR agonists rescued LTP
that was deficient in BACE1 knock-out mice, but had very little
effect on LTP in wildtype mice [112]. The rescue by a7 nAChR
agonists was abolished by blockers of ryanodine-sensitive calcium
stores, suggesting that calcium-induced calcium release played a
key role in this regulation. However, the effect of a7 nAChR
activation on STP needs to be tested on mossy fiber transmission.
These studies also pointed to a calcium rise induced by a7 nAChR
activation as the central mechanism for these actions, and a7
nAChR activation also triggers differential signaling molecules to
produce various influences in the hippocampus.
4. a7 Activation via cholinergic synapses in the hippocampus
Under physiological conditions, a7 nAChRs are activated by
endogenous ACh released from cholinergic neurons. The primary
cholinergic input to the hippocampus arises from the medial
septum and diagonal band of Broca [8,28], although a small
population of cholinergic interneurons do exist in the hippocam-
pus as recently re-confirmed from ChAT-tauGFP and ChAT-CRE/
Rosa-YFP transgenic mice [120]. Initial studies using electrical
cholinergic stimulation to dissect the function of endogenous ACh
showed prominent muscarinic receptor's effect of Schaffer
collateral input to CA1 pyramidal neurons [35]. The a7 nAChR-
dependent modulation of synaptic plasticity of CA3-CA1 gluta-
matergic synapses was uncovered with localized application of
ACh, which is sensitive to the location and timing of a7 nAChR
activation [57,42]. The development of optogenetic techniques
allows both cell-type specific and temporally precise stimulation
of cholinergic inputs to the hippocampus. Taking advantage of this
approach, our lab investigated how activation of endogenous
cholinergic inputs may regulate hippocampal synaptic plasticity
[47]. We found that a7 nAChRs mediated two forms of
hippocampal synaptic plasticity with a timing precision in the
millisecond range. When the cholinergic input to the CA1
hippocampal region was activated 100 ms prior to activation of
the Schaffer collateral (SC) pathway, this induced an a7 nAChR-
dependent form of LTP. When the cholinergic input was activated
only 10 ms prior to the SC pathway, this induced an a7 nAChR-
dependent short-term depression (STD) that was mediated
primarily through the presynaptic inhibition of glutamate release.
Furthermore, we observed a7 nAChR-dependent enhancement of
calcium responses during this LTP both pre- and post synaptically,
and short-term depression of calcium responses during STD [46].
In aged a7-nAChR KO mice, both evoked field synaptic potentials
Please cite this article in press as: Q. Cheng, J.L. Yakel, The effect of a7 nicotinic receptor activation on glutamatergic transmission in the
hippocampus, Biochem Pharmacol (2015), http://dx.doi.org/10.1016/j.bcp.2015.07.015
3
and LTP were significantly reduced in hippocampal CA3-CA1
synapses [75], suggesting that cholinergic modulation of LTP
required the activation of a7 nAChRs.
5. Second messenger signaling upon activation of a7 nAChRs-
The a7 nAChRs have a high calcium permeability, comparable
to that of NMDA receptors [97,110]; this confers the ability of a7
nAChRs to produce long-lasting modulations of synaptic trans-
mission [30,78]. The intracellular calcium rise alters the amount of
neurotransmitter release directly [85], and triggers multiple
signaling cascades to modify the efficacy of synaptic transmission.
Indeed, we observed a prominent calcium rise upon activation of
a7 nAChRs at mossy fiber terminals (using the genetically-
encoded calcium sensor GCaMP3), and found that the peak of the
action potential (AP)-evoked calcium transient was enhanced by
the a7 nAChR agonist PNU-282987 [15,16]. Similar actions of
presynaptic a7 nAChRs on AP-evoked calcium transients were also
reported in CA1 pyramidal neurons [108]. Changes in the AP-
induced calcium transients would lead to changes in the amount of
neurotransmitter released at presynaptic terminals [56]. The
source of the calcium increase would be mainly comprised of
the calcium influx directly through the a7 nAChR itself [32,43], and
any calcium-induced calcium release from intracellular calcium
stores [115,100,99]. Although calcium influx through voltage-gated
calcium channels (VGCC) previously was shown not to contribute
significantly to the a7 nAChR-mediated presynaptic effect [26],
other studies reported that calcium influx through VGCCs could
contribute to some degree [11,33,23]. In addition, recent studies
showed that a7 nAChR activation enhanced NMDAR-mediated
whole-cell currents and glutamate release from hippocampal
synaptosomes [123,72]. Lastly, membrane depolarization induced
by a7 nAChR activation could release the magnesium blockade of
NMDARs to reduce the threshold for NMDAR-dependent synaptic
plasticity (Fig. 1).
Although activation of the a7 nAChRs induces transient calcium
rises, the kinetics of this do not explain the long-lasting effects
caused by a7 nAChR agonists on synaptic plasticity [68,124,125].
Many calcium signaling cascades have been linked to a7 nAChRs,
including the CaMKII [99] and cAMP-PKA pathways [20,116].
Fig. 1. Mechanisms of a7 nAChR-mediated presynaptic enhancement of glutamate
release. The intracellular calcium level at presynaptic terminals is increased by
calcium influx through a7 nAChRs, VGCCs, and NMDARs from the outside, and
calcium release from intracellular calcium stores. The raised calcium levels could
increase vesicular glutamate release directly, and trigger cAMP-PKA-dependent
pathways for prolonged enhancement of glutamate release. Phosphorylation of
synapsins by PKA leads to synaptic vesicle mobilization from the reserve pool to the
readily releasable pool, hence increasing glutamate release. (Purple trapeziods
depict unphosphorylated synapsins, while red trapezoids depict phosphorylated
synapsins).
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Recently, we reported that the action of a7 nAChRs at mossy fiber
terminals depended on PKA activity [15]. Since it was shown that
the a7 nAChR and adenylyl cyclase 1 (AC1) are associated
physically and functionally in epithelium [77], we investigated
any connection between the activation of the a7 nAChR and cAMP
signaling in hippocampal neurons. Using a FRET-based cAMP
sensor, we found that activation of a7 nAChRs significantly
increased intracellular cAMP levels. The cAMP rise was abolished
by the a7 nAChR antagonist MLA, the calcium chelator BAPTA, the
selective AC1 inhibitor CB-6673567, and siRNA-mediated AC1
knockdown; this suggested that the calcium-dependent AC1 is
required for linking the activation of a7 nAChRs to a cAMP rise [16].
We also found that the activation of a7 nAChRs leads to the
widespread increase of phosphorylated synapsin I (via its PKA site),
which is a prominent presynaptic PKA substrate [55] and can
regulate neurotransmitter release and calcium-dependent synap-
tic plasticity [51,50,80,36,18]. The PKA pathway was also shown to
be required for the a7 nAChR-mediated enhancement of LTP in
dentate granule cells [116]. Moreover, a7 nAChR activation was
shown to interact with G proteins and G protein-regulated inducer
of neurite outgrowth 1 to reduce axonal growth [86,87]. With the
advancement of new technologies, novel signaling pathways might
be linked to a7 nAChRs to interpret its complex actions in the
brain.
6. Significance and conclusion
The changes in a7 nAChR expression and density in the
hippocampus have been observed in many cognitive impairment
disorders, such as schizophrenia [37] and Alzheimer’s disease
[21,27,95]. However, the physiological mechanism and consequen-
ces of these changes are still unclear, in terms of how these
receptors regulate neuronal excitability, synaptic plasticity and
brain circuit function. Furthermore, the outcome of a7 nAChR
activation on the hippocampal circuit is complicated by the
extensive distribution of a7 nAChRs on both glutamatergic and
GABAergic neurons. With the newly-generated floxed a7 nAChR
transgenic mouse [48] combining with Cre and Cre-ER dependent
systems, selective deletion of a7 nAChRs from distinct cell
populations at specific developmental stages will allow us to
unravel systematically the impact of a7 nAChR activation on
hippocampal network both in vitro and in vivo. This will also help
us to understand how the alteration of a7 nAChR function will
impact cognitive function.
The agonists and modulators of a7 nAChRs have been attractive
candidates for developing therapeutic treatments for these
neuronal disorders [25,24]. Indeed, several drugs targeting a7
nAChRs demonstrated their potential in treating schizophrenic
patients [38,92,63]. With the development of improved biosensors
and emerging tools such as optogenetics (combined with
electrophysiology), we will continue to probe cellular and
molecular mechanisms of a7 nAChR’s functions in neural circuits.
The insights gained from these studies will lead to new treatments
to mitigate cognitive impairments.
Acknowledgements
We would like to thank Drs. Serena Dudek and Christian
Erxleben for the helpful reading and suggestions on our manu-
script. This research was funded by the NIEHS Intramural Research
Program/NIH. The authors declare no competing financial inter-
ests.
Please cite this article in press as: Q. Cheng, J.L. Yakel, The effect of a7 nicotinic receptor activation on glutamatergic transmission in the
hippocampus, Biochem Pharmacol (2015), http://dx.doi.org/10.1016/j.bcp.2015.07.015
References
[1] C.E. Adams, Comparison of alpha7 nicotinic acetylcholine receptor
development in the hippocampal formation of C3H and DBA/2 mice, Brain
Res. Dev. Brain Res. 143 (2003) 137–149.
[2] C.E. Adams, R.S. Broide, Y. Chen, U.H. Winzer-Serhan, T.A. Henderson, F.M.
Leslie, R. Freedman, Development of the alpha7 nicotinic cholinergic receptor
in rat hippocampal formation, Brain Res. Dev. Brain Res. 139 (2002) 175–187.
[3] C.E. Adams, R.S. Broide, Y. Chen, U.H. Winzer-Serhan, T.A. Henderson, F.M.
Leslie, R. Freedman, Development of the alpha7 nicotinic cholinergic receptor
in rat hippocampal formation, Brain Res. Dev. Brain Res. 139 (2002) 175–187.
[4] C.E. Adams, J.C. Yonchek, J.A. Stitzel, Development of hippocampal alpha7
nicotinic receptors in C3H and DBA/2 congenic mice, Brain Res. 1122 (2006)
27–35.
[5] E.X. Albuquerque, E.F. Pereira, M. Alkondon, S.W. Rogers a), Mammalian
nicotinic acetylcholine receptors: from structure to function, Physiol. Rev. 89
(2009) 73–120.
[6] E.X. Albuquerque, E.F. Pereira, M. Alkondon, S.W. Rogers b), Mammalian
nicotinic acetylcholine receptors: from structure to function, Physiol. Rev. 89
(2009) 73–120.
[7] M. Alkondon, E.X. Albuquerque, The nicotinic acetylcholine receptor
subtypes and their function in the hippocampus and cerebral cortex, Prog.
Brain Res. 145 (2004) 109–120.
[8] D.G. Amaral, J. Kurz, An analysis of the origins of the cholinergic and
noncholinergic septal projections to the hippocampal formation of the rat, J.
Comp. Neurol. 240 (1985) 37–59.
[9] R. Anand, X. Peng, J. Lindstrom, Homomeric and native alpha 7 acetylcholine
receptors exhibit remarkably similar but non-identical pharmacological
properties, suggesting that the native receptor is a heteromeric protein
complex, FEBS Lett. 327 (1993) 241–246.
[10] C.J. Baier, M.E. Pallares, E. Adrover, M.C. Monteleone, M.A. Brocco, F.J.
Barrantes, M.C. Antonelli, Prenatal restraint stress decreases the expression
of alpha-7 nicotinic receptor in the brain of adult rat offspring, Stress (2015)
1–11.
[11] G.E. Barrantes, C.T. Murphy, J. Westwick, S. Wonnacott, Nicotine increases
intracellular calcium in rat hippocampal neurons via voltage-gated calcium
channels, Neurosci. Lett. 196 (1995) 101–104.
[12] D. Bertrand, J.L. Galzi, A. Devillers-Thiery, S. Bertrand, J.P. Changeux,
Mutations at two distinct sites within the channel domain M2 alter calcium
permeability of neuronal alpha 7 nicotinic receptor, Proc. Natl. Acad. Sci. U. S.
A. 90 (1993) 6971–6975.
[13] R.S. Bitner, W.H. Bunnelle, D.J. Anderson, C.A. Briggs, J. Buccafusco, P. Curzon,
M.W. Decker, J.M. Frost, J.H. Gronlien, E. Gubbins, J. Li, J. Malysz, S. Markosyan,
K. Marsh, M.D. Meyer, A.L. Nikkel, R.J. Radek, H.M. Robb, D. Timmermann, J.P.
Sullivan, M. Gopalakrishnan, Broad-spectrum efficacy across cognitive
domains by alpha7 nicotinic acetylcholine receptor agonism correlates with
activation of ERK1/2 and CREB phosphorylation pathways, J. Neurosci. 27
(2007) 10578–10587.
[14] M.G. Blake, M.C. Krawczyk, C.M. Baratti, M.M. Boccia, Neuropharmacology of
memory consolidation and reconsolidation: insights on central cholinergic
mechanisms, J. Physiol. Paris 108 (2014) 286–291.
[15] Q. Cheng, J.L. Yakel, Presynaptic alpha7 nicotinic acetylcholine receptors
enhance hippocampal mossy fiber glutamatergic transmission via PKA
activation, J. Neurosci. 34 (2014) 124–133.
[16] Q. Cheng, J.L. Yakel, Activation of alpha7 nicotinic acetylcholine receptors
increases intracellular cAMP levels via activation of AC1 in hippocampal
neurons, Neuropharmacology 95 (August) (2015) 405–414.
[17] J.J. Couey, R.M. Meredith, S. Spijker, R.B. Poorthuis, A.B. Smit, A.B. Brussaard,
H.D. Mansvelder, Distributed network actions by nicotine increase the
threshold for spike-timing-dependent plasticity in prefrontal cortex, Neuron
54 (2007) 73–87.
[18] M.A. Cousin, G.J. Evans, Activation of silent and weak synapses by cAMP-
dependent protein kinase in cultured cerebellar granule neurons, J. Physiol.
589 (2011) 1943–1955.
[19] F. Dajas-Bailador, S. Wonnacott, Nicotinic acetylcholine receptors and the
regulation of neuronal signalling, Trends Pharmacol. Sci. 25 (2004) 317–324.
[20] F.A. Dajas-Bailador, L. Soliakov, S. Wonnacott, Nicotine activates the
extracellular signal-regulated kinase 1/2 via the alpha7 nicotinic
acetylcholine receptor and protein kinase A, in SH-SY5Y cells and
hippocampal neurones, J. Neurochem. 80 (2002) 520–530.
[21] J.A. Dani, D. Bertrand, Nicotinic acetylcholine receptors and nicotinic
cholinergic mechanisms of the central nervous system, Annu. Rev.
Pharmacol. Toxicol. 47 (2007) 699–729.
[22] J. de Leon, F.J. Diaz, A meta-analysis of worldwide studies demonstrates an
association between schizophrenia and tobacco smoking behaviors,
Schizophr. Res. 76 (2005) 135–157.
[23] L. del Barrio, J. Egea, R. Leon, A. Romero, A. Ruiz, M. Montero, J. Alvarez, M.G.
Lopez, Calcium signalling mediated through alpha7 and non-alpha7 nAChR
stimulation is differentially regulated in bovine chromaffin cells to induce
catecholamine release, Br. J. Pharmacol. 162 (2011) 94–110.
[24] S.I. Deutsch, J.A. Burket, A.D. Benson, Targeting the alpha nicotinic
acetylcholine receptor to prevent progressive dementia and improve
cognition in adults with Down’s syndrome, Prog. Neuropsychopharmacol.
Biol. Psychiatry 54C (2014) 131–139.
G Model
BCP 12308 No. of Pages 6
Q. Cheng, J.L. Yakel / Biochemical Pharmacology xxx (2015) xxx–xxx
[25] S.I. Deutsch, B.L. Schwartz, N.R. Schooler, C.H. Brown, R.B. Rosse, S.M. Rosse,
Targeting alpha-7 nicotinic neurotransmission in schizophrenia: a novel
agonist strategy, Schizophr. Res. 148 (2013) 138–144.
[26] J.A. Dickinson, J.N. Kew, S. Wonnacott, Presynaptic alpha 7- and beta 2-
containing nicotinic acetylcholine receptors modulate excitatory amino acid
release from rat prefrontal cortex nerve terminals via distinct cellular
mechanisms, Mol. Pharmacol. 74 (2008) 348–359.
[27] K.T. Dineley, A.A. Pandya, J.L. Yakel, Nicotinic ACh receptors as therapeutic
targets in CNS disorders, Trends Pharmacol. Sci. 36 (2015) 96–108.
[28] P. Dutar, M.H. Bassant, M.C. Senut, Y. Lamour, The septohippocampal
pathway: structure and function of a central cholinergic system, Physiol. Rev.
75 (1995) 393–427.
[29] R. Fabian-Fine, P. Skehel, M.L. Errington, H.A. Davies, E. Sher, M.G. Stewart, A.
Fine, Ultrastructural distribution of the alpha7 nicotinic acetylcholine
receptor subunit in rat hippocampus, J. Neurosci. 21 (2001) 7993–8003.
[30] Z.M. Fagen, H.D. Mansvelder, J.R. Keath, D.S. McGehee, Short- and long-term
modulation of synaptic inputs to brain reward areas by nicotine, Ann. N. Y.
Acad. Sci. 1003 (2003) 185–195.
[31] D. Fayuk, J.L. Yakel, Ca2+ permeability of nicotinic acetylcholine receptors in
rat hippocampal CA1 interneurones, J. Physiol. 566 (2005) 759–768.
[32] D. Fayuk, J.L. Yakel, Dendritic Ca2+ signalling due to activation of alpha 7-
containing nicotinic acetylcholine receptors in rat hippocampal neurons, J.
Physiol. 582 (2007) 597–611.
[33] D. Fayuk, J.L. Yakel, Dendritic Ca2+ signalling due to activation of alpha 7-
containing nicotinic acetylcholine receptors in rat hippocampal neurons, J.
Physiol. 582 (2007) 597–611.
[34] C. Fernandes, E. Hoyle, E. Dempster, L.C. Schalkwyk, D.A. Collier, Performance
deficit of alpha7 nicotinic receptor knockout mice in a delayed matching-to-
place task suggests a mild impairment of working/episodic-like memory,
Genes Brain Behav. 5 (2006) 433–440.
[35] D. Fernandez de Sevilla, W. Buno, Presynaptic inhibition of Schaffer collateral
synapses by stimulation of hippocampal cholinergic afferent fibres, Eur. J.
Neurosci. 17 (2003) 555–558.
[36] F. Fiumara, C. Milanese, A. Corradi, S. Giovedi, G. Leitinger, A. Menegon, P.G.
Montarolo, F. Benfenati, M. Ghirardi, Phosphorylation of synapsin domain A
is required for post-tetanic potentiation, J. Cell Sci. 120 (2007) 3228–3237.
[37] R. Freedman, D. Goldowitz, Studies on the hippocampal formation: From
basic development to clinical applications: Studies on schizophrenia, Prog.
Neurobiol. 90 (2010) 263–275.
[38] R. Freedman, A. Olincy, R.W. Buchanan, J.G. Harris, J.M. Gold, L. Johnson, D.
Allensworth, A. Guzman-Bonilla, B. Clement, M.P. Ball, J. Kutnick, V. Pender, L.
F. Martin, K.E. Stevens, B.D. Wagner, G.O. Zerbe, F. Soti, W.R. Kem, Initial phase
2 trial of a nicotinic agonist in schizophrenia, Am. J. Psychiatry 165 (2008)
1040–1047.
[39] S. Fujii, Z. Ji, N. Morita, K. Sumikawa, Acute and chronic nicotine exposure
differentially facilitate the induction of LTP, Brain Res. 846 (1999) 137–143.
[40] S. Fujii, K. Sumikawa, Nicotine accelerates reversal of long-term potentiation
and enhances long-term depression in the rat hippocampal CA1 region, Brain
Res. 894 (2001) 340–346.
[41] J. Gault, J. Hopkins, R. Berger, C. Drebing, J. Logel, C. Walton, M. Short, R.
Vianzon, A. Olincy, R.G. Ross, L.E. Adler, R. Freedman, S. Leonard, Comparison
of polymorphisms in the alpha7 nicotinic receptor gene and its partial
duplication in schizophrenic and control subjects, Am. J. Med. Genet. B:
Neuropsychiatr. Genet. 123B (2003) 39–49.
[42] S. Ge, J.A. Dani, Nicotinic acetylcholine receptors at glutamate synapses
facilitate long-term depression or potentiation, J. Neurosci. 25 (2005) 6084–
6091.
[43] D. Gilbert, M. Lecchi, S. Arnaudeau, D. Bertrand, N. Demaurex, Local and
global calcium signals associated with the opening of neuronal alpha7
nicotinic acetylcholine receptors, Cell Calcium 45 (2009) 198–207.
[44] R. Gray, A.S. Rajan, K.A. Radcliffe, M. Yakehiro, J.A. Dani, Hippocampal
synaptic transmission enhanced by low concentrations of nicotine, Nature
383 (1996) 713–716.
[45] M.J. Grybko, E.T. Hahm, W. Perrine, J.A. Parnes, W.S. Chick, G. Sharma, T.E.
Finger, S. Vijayaraghavan, A transgenic mouse model reveals fast nicotinic
transmission in hippocampal pyramidal neurons, Eur. J. Neurosci. 33 (2011)
1786–1798.
[46] Z. Gu, P.W. Lamb, J.L. Yakel, Cholinergic coordination of presynaptic and
postsynaptic activity induces timing-dependent hippocampal synaptic
plasticity, J. Neurosci. 32 (2012) 12337–12348.
[47] Z. Gu, J.L. Yakel, Timing-dependent septal cholinergic induction of dynamic
hippocampal synaptic plasticity, Neuron 71 (2011) 155–165.
[48] C.M. Hernandez, I. Cortez, Z. Gu, J.O. Colon-Saez, P.W. Lamb, M. Wakamiya, J.L.
Yakel, K.T. Dineley, Research tool: validation of floxed alpha7 nicotinic
acetylcholine receptor conditional knockout mice using in vitro and in vivo
approaches, J. Physiol. 592 (2014) 3201–3214.
[49] C.M. Hernandez, R. Kayed, H. Zheng, J.D. Sweatt, K.T. Dineley, Loss of alpha7
nicotinic receptors enhances beta-amyloid oligomer accumulation,
exacerbating early-stage cognitive decline and septohippocampal pathology
in a mouse model of Alzheimer’s disease, J. Neurosci. 30 (2010) 2442–2453.
[50] S. Hilfiker, F. Benfenati, F. Doussau, A.C. Nairn, A.J. Czernik, G.J. Augustine, P.
Greengard, Structural domains involved in the regulation of transmitter
release by synapsins, J. Neurosci. 25 (2005) 2658–2669.
[51] S. Hilfiker, V.A. Pieribone, A.J. Czernik, H.T. Kao, G.J. Augustine, P. Greengard,
Synapsins as regulators of neurotransmitter release, Philos. Trans. R. Soc.
Lond. B: Biol. Sci. 354 (1999) 269–279.
Please cite this article in press as: Q. Cheng, J.L. Yakel, The effect of a7 nicotinic receptor activation on glutamatergic transmission in the
hippocampus, Biochem Pharmacol (2015), http://dx.doi.org/10.1016/j.bcp.2015.07.015
5
[52] P.G. Hoffmeister, C.K. Donat, M.U. Schuhmann, C. Voigt, B. Walter, K. Nieber, J.
Meixensberger, R. Bauer, P. Brust, Traumatic brain injury elicits similar
alterations in alpha7 nicotinic receptor density in two different experimental
models, Neuromol. Med. 13 (2011) 44–53.
[53] L.T. Huang, J.L. Sherwood, Y.J. Sun, D. Lodge, Y. Wang, Activation of
presynaptic alpha7 nicotinic receptors evokes an excitatory response in
hippocampal CA3 neurones in anaesthetized rats: an in vivo iontophoretic
study, Br. J. Pharmacol. 159 (2010) 554–565.
[54] B.E. Hunter, C.M. de Fiebre, R.L. Papke, W.R. Kem, E.M. Meyer, A novel
nicotinic agonist facilitates induction of long-term potentiation in the rat
hippocampus, Neurosci. Lett. 168 (1994) 130–134.
[55] W.B. Huttner, P. Greengard, Multiple phosphorylation sites in protein I and
their differential regulation by cyclic AMP and calcium, Proc. Natl. Acad. Sci.
U. S. A. 76 (1979) 5402–5406.
[56] M.B. Jackson, A. Konnerth, G.J. Augustine, Action potential broadening and
frequency-dependent facilitation of calcium signals in pituitary nerve
terminals, Proc. Natl. Acad. Sci. U. S. A. 88 (1991) 380–384.
[57] D. Ji, R. Lape, J.A. Dani, Timing and location of nicotinic activity enhances or
depresses hippocampal synaptic plasticity, Neuron 31 (2001) 131–141.
[58] D. John, I. Shelukhina, Y. Yanagawa, J. Deuchars, Z. Henderson, Functional
alpha7 nicotinic receptors are expressed on immature granule cells of the
postnatal dentate gyrus, Brain Res. 1601 (2015) 15–30.
[59] S. Jones, S. Sudweeks, J.L. Yakel, Nicotinic receptors in the brain: correlating
physiology with function, Trends Neurosci. 22 (1999) 555–561.
[60] S. Jones, J.L. Yakel, Inhibitory interneurons in hippocampus, Cell Biochem.
Biophys. 31 (1999) 207–218.
[61] P. Kasa, I. Hlavati, E. Dobo, A. Wolff, F. Joo, J.R. Wolff, Synaptic and non-
synaptic cholinergic innervation of the various types of neurons in the main
olfactory bulb of adult rat: immunocytochemistry of choline
acetyltransferase, Neuroscience 67 (1995) 667–677.
[62] H. Kawai, W. Zago, D.K. Berg, Nicotinic alpha 7 receptor clusters on
hippocampal GABAergic neurons: regulation by synaptic activity and
neurotrophins, J. Neurosci. 22 (2002) 7903–7912.
[63] R.S. Keefe, H.A. Meltzer, N. Dgetluck, M. Gawryl, G. Koenig, H.J. Moebius, I.
Lombardo, D.C. Hilt, Randomized, double-blind, placebo-controlled study of
encenicline, an alpha-7 nicotinic acetylcholine receptor agonist as a
treatment for cognitive impairment in schizophrenia,
Neuropsychopharmacology (2015) .
[64] S.S. Khiroug, P.C. Harkness, P.W. Lamb, S.N. Sudweeks, L. Khiroug, N.S. Millar, J.
L. Yakel, Rat nicotinic ACh receptor alpha7 and beta2 subunits co-assemble to
form functional heteromeric nicotinic receptor channels, J. Physiol. 540
(2002) 425–434.
[65] K.S. Kroker, G. Rast, H. Rosenbrock, Differential effects of subtype-specific
nicotinic acetylcholine receptor agonists on early and late hippocampal LTP,
Eur. J. Pharmacol. 671 (2011) 26–32.
[66] P.W. Lamb, M.A. Melton, J.L. Yakel, Inhibition of neuronal nicotinic
acetylcholine receptor channels expressed in Xenopus oocytes by beta-
amyloid1-42 peptide, J. Mol. Neurosci. 27 (2005) 13–21.
[67] C. Le Magueresse, V. Safiulina, J.P. Changeux, E. Cherubini, Nicotinic
modulation of network and synaptic transmission in the immature
hippocampus investigated with genetically modified mice, J. Physiol. 576
(2006) 533–546.
[68] C. Lena, J.P. Changeux, Role of Ca2+ ions in nicotinic facilitation of GABA
release in mouse thalamus, J. Neurosci. 17 (1997) 576–585.
[69] E.D. Levin, A. Bradley, N. Addy, N. Sigurani, Hippocampal alpha 7 and alpha 4
beta 2 nicotinic receptors and working memory, Neuroscience 109 (2002)
757–765.
[70] E.D. Levin, A. Petro, A.H. Rezvani, N. Pollard, N.C. Christopher, M. Strauss, J.
Avery, J. Nicholson, J.E. Rose, Nicotinic alpha7- or beta2-containing receptor
knockout: effects on radial-arm maze learning and long-term nicotine
consumption in mice, Behav. Brain Res 196 (2009) 207–213.
[71] E.D. Levin, W. Wilson, J.E. Rose, J. McEvoy, Nicotine-haloperidol interactions
and cognitive performance in schizophrenics, Neuropsychopharmacology 15
(1996) 429–436.
[72] S. Li, Q. Nai, T.V. Lipina, J.C. Roder, F. Liu, alpha7nAchR/NMDAR coupling
affects NMDAR function and object recognition, Mol. Brain 6 (2013) 58.
[73] Q. Liu, Y. Huang, F. Xue, A. Simard, J. DeChon, G. Li, J. Zhang, L. Lucero, M.
Wang, M. Sierks, G. Hu, Y. Chang, R.J. Lukas, J. Wu, A novel nicotinic
acetylcholine receptor subtype in basal forebrain cholinergic neurons with
high sensitivity to amyloid peptides, J. Neurosci. 29 (2009) 918–929.
[74] Q. Liu, H. Kawai, D.K. Berg, beta -Amyloid peptide blocks the response of
alpha 7-containing nicotinic receptors on hippocampal neurons, Proc. Natl.
Acad. Sci. U. S. A. 98 (2001) 4734–4739.
[75] L. Ma, D. Turner, J. Zhang, Q. Wang, M. Wang, J. Shen, S. Zhang, J. Wu, Deficits
of synaptic functions in hippocampal slices prepared from aged mice null
alpha7 nicotinic acetylcholine receptors, Neurosci. Lett. 570 (2014) 97–101.
[76] L. Maggi, C. Le Magueresse, J.P. Changeux, E. Cherubini, Nicotine activates
immature silent connections in the developing hippocampus, Proc. Natl.
Acad. Sci. U. S. A. 100 (2003) 2059–2064.
[77] K. Maouche, K. Medjber, J.M. Zahm, F. Delavoie, C. Terryn, C. Coraux, S. Pons, I.
Cloez-Tayarani, U. Maskos, P. Birembaut, J.M. Tournier, Contribution of alpha7
nicotinic receptor to airway epithelium dysfunction under nicotine exposure,
Proc. Natl. Acad. Sci. U. S. A. 110 (2013) 4099–4104.
[78] B.E. McKay, A.N. Placzek, J.A. Dani, Regulation of synaptic transmission and
plasticity by neuronal nicotinic acetylcholine receptors, Biochem. Pharmacol.
74 (2007) 1120–1133.
G Model
BCP 12308 No. of Pages 6
6 Q. Cheng, J.L. Yakel / Biochemical Pharmacology xxx (2015) xxx–xxx
[79] A.R. McQuiston, D.V. Madison, Nicotinic receptor activation excites distinct
subtypes of interneurons in the rat hippocampus, J. Neurosci. 19 (1999)
2887–2896.
[80] A. Menegon, D. Bonanomi, C. Albertinazzi, F. Lotti, G. Ferrari, H.T. Kao, F.
Benfenati, P. Baldelli, F. Valtorta, Protein kinase A-mediated synapsin I
phosphorylation is a central modulator of Ca2+-dependent synaptic activity,
J. Neurosci. 26 (2006) 11670–11681.
[81] D.D. Mowrey, Q. Liu, V. Bondarenko, Q. Chen, E. Seyoum, Y. Xu, J. Wu, P. Tang,
Insights into distinct modulation of alpha7 and alpha7beta2 nicotinic
acetylcholine receptors by the volatile anesthetic isoflurane, J. Biol. Chem.
288 (2013) 35793–35800.
[82] T.A. Murray, D. Bertrand, R.L. Papke, A.A. George, R. Pantoja, R. Srinivasan, Q.
Liu, J. Wu, P. Whiteaker, H.A. Lester, R.J. Lukas, alpha7beta2 nicotinic
acetylcholine receptors assemble, function, and are activated primarily via
their alpha7-alpha7 interfaces, Mol. Pharmacol. 81 (2012) 175–188.
[83] S. Nakauchi, K. Sumikawa, Endogenous ACh suppresses LTD induction and
nicotine relieves the suppression via different nicotinic ACh receptor
subtypes in the mouse hippocampus, Life Sci. 111 (2014) 62–68.
[84] R. Nashmi, H.A. Lester, CNS localization of neuronal nicotinic receptors, J. Mol.
Neurosci. 30 (2006) 181–184.
[85] E. Neher, T. Sakaba, Multiple roles of calcium ions in the regulation of
neurotransmitter release, Neuron 59 (2008) 861–872.
[86] J.C. Nordman, N. Kabbani, Microtubule dynamics at the growth cone are
mediated by alpha7 nicotinic receptor activation of a Galphaq and IP3
receptor pathway, FASEB J. 28 (2014) 2995–3006.
[87] J.C. Nordman, W.S. Phillips, N. Kodama, S.G. Clark, C.A. Del Negro, N. Kabbani,
Axon targeting of the alpha 7 nicotinic receptor in developing hippocampal
neurons by Gprin1 regulates growth, J. Neurochem. 129 (2014) 649–662.
[88] A. Nott, E.D. Levin, Dorsal hippocampal alpha7 and alpha4beta2 nicotinic
receptors and memory, Brain Res. 1081 (2006) 72–78.
[89] T. Ondrejcak, Q. Wang, J.N. Kew, D.J. Virley, N. Upton, R. Anwyl, M.J. Rowan,
Activation of alpha7 nicotinic acetylcholine receptors persistently enhances
hippocampal synaptic transmission and prevents Ass-mediated inhibition of
LTP in the rat hippocampus, Eur. J. Pharmacol. 677 (2012) 63–70.
[90] E. Palma, L. Maggi, B. Barabino, F. Eusebi, M. Ballivet, Nicotinic acetylcholine
receptors assembled from the alpha7 and beta3 subunits, J. Biol. Chem. 274
(1999) 18335–18340.
[91] D.L. Pettit, Z. Shao, J.L. Yakel, beta-Amyloid(1-42) peptide directly modulates
nicotinic receptors in the rat hippocampal slice, J. Neurosci. 21 (2001)
RC120.
[92] S.H. Preskorn, M. Gawryl, N. Dgetluck, M. Palfreyman, L.O. Bauer, D.C. Hilt,
Normalizing effects of EVP-6124, an alpha-7 nicotinic partial agonist, on
event-related potentials and cognition: a proof of concept, randomized trial
in patients with schizophrenia, J. Psychiatr. Pract. 20 (2014) 12–24.
[93] K.A. Radcliffe, J.A. Dani, Nicotinic stimulation produces multiple forms of
increased glutamatergic synaptic transmission, J. Neurosci. 18 (1998)
7075–7083.
[94] F. Rubboli, J.A. Court, C. Sala, C. Morris, B. Chini, E. Perry, F. Clementi,
Distribution of nicotinic receptors in the human hippocampus and thalamus,
Eur. J. Neurosci. 6 (1994) 1596–1604.
[95] S. Sadigh-Eteghad, A. Majdi, M. Talebi, J. Mahmoudi, S. Babri, Regulation of
nicotinic acetylcholine receptors in Alzheimers disease: a possible role of
chaperones, Eur. J. Pharmacol. 755 (2015) 34–41.
[96] P.B. Sargent, The diversity of neuronal nicotinic acetylcholine receptors,
Annu. Rev. Neurosci. 16 (1993) 403–443.
[97] P. Seguela, J. Wadiche, K. Dineley-Miller, J.A. Dani, J.W. Patrick, Molecular
cloning, functional properties, and distribution of rat brain alpha 7: a
nicotinic cation channel highly permeable to calcium, J. Neurosci. 13 (1993)
596–604.
[98] Z. Shao, J.L. Yakel, Single channel properties of neuronal nicotinic ACh
receptors in stratum radiatum interneurons of rat hippocampal slices, J.
Physiol. 527 (Pt 3) (2000) 507–513.
[99] G. Sharma, M. Grybko, S. Vijayaraghavan, Action potential-independent and
nicotinic receptor-mediated concerted release of multiple quanta at
hippocampal CA3-mossy fiber synapses, J. Neurosci. 28 (2008) 2563–2575.
[100] G. Sharma, S. Vijayaraghavan, Modulation of presynaptic store calcium
induces release of glutamate and postsynaptic firing, Neuron 38 (2003)
929–939.
[101] J.X. Shen, J.L. Yakel, Nicotinic acetylcholine receptor-mediated calcium
signaling in the nervous system, Acta Pharmacol. Sin. 30 (2009)
673–680.
[102] J.X. Shen, J.L. Yakel, Functional alpha7 nicotinic ACh receptors on astrocytes in
rat hippocampal CA1 slices, J Mol Neurosci 48 (2012) 14–21.
[103] M.L. Sinkus, S. Graw, R. Freedman, R.G. Ross, H.A. Lester, S. Leonard, The
human CHRNA7 and CHRFAM7A genes: a review of the genetics, regulation,
and function, Neuropharmacology (2015) .
Please cite this article in press as: Q. Cheng, J.L. Yakel, The effect of a7 nicotinic receptor activation on glutamatergic transmission in the
hippocampus, Biochem Pharmacol (2015), http://dx.doi.org/10.1016/j.bcp.2015.07.015
[104] M.L. Sinkus, S. Graw, R. Freedman, R.G. Ross, H.A. Lester, S. Leonard), The
human CHRNA7 and CHRFAM7A genes: a review of the genetics, regulation,
and function, Neuropharmacology 96 (2015) 274–288.
[105] M.L. Sinkus, M.J. Lee, J. Gault, J. Logel, M. Short, R. Freedman, S.L. Christian, J.
Lyon, S. Leonard, A 2-base pair deletion polymorphism in the partial
duplication of the alpha7 nicotinic acetylcholine gene (CHRFAM7A) on
chromosome 15q14 is associated with schizophrenia, Brain Res. 1291 (2009)
1–11.
[106] E. Sola, S. Capsoni, M. Rosato-Siri, A. Cattaneo, E. Cherubini, Failure of
nicotine-dependent enhancement of synaptic efficacy at Schaffer-collateral
CA1 synapses of AD11 anti-nerve growth factor transgenic mice, Eur. J.
Neurosci. 24 (2006) 1252–1264.
[107] S.N. Sudweeks, J.L. Yakel, Functional and molecular characterization of
neuronal nicotinic ACh receptors in rat CA1 hippocampal neurons, J. Physiol.
527 (Pt 3) (2000) 515–528.
[108] S.I. Szabo, T. Zelles, E.S. Vizi, B. Lendvai, The effect of nicotine on spiking
activity and Ca2+ dynamics of dendritic spines in rat CA1 pyramidal neurons,
Hippocampus 18 (2008) 376–385.
[109] D.B. Timmermann, J.H. Gronlien, K.L. Kohlhaas, E.O. Nielsen, E. Dam, T.D.
Jorgensen, P.K. Ahring, D. Peters, D. Holst, J.K. Christensen, J. Malysz, C.A.
Briggs, M. Gopalakrishnan, G.M. Olsen, An allosteric modulator of the alpha7
nicotinic acetylcholine receptor possessing cognition-enhancing properties
in vivo, J. Pharmacol. Exp. Ther. 323 (2007) 294–307.
[110] V.V. Uteshev, alpha7 nicotinic ACh receptors as a ligand-gated source of
Ca(2+) ions: the search for a Ca(2+) optimum, Adv. Exp. Med. Biol. 740 (2012)
603–638.
[111] E. Wada, K. Wada, J. Boulter, E. Deneris, S. Heinemann, J. Patrick, L.W.
Swanson, Distribution of alpha 2, alpha 3, alpha 4, and beta 2 neuronal
nicotinic receptor subunit mRNAs in the central nervous system: a
hybridization histochemical study in the rat, J. Comp. Neurol. 284 (1989)
314–335.
[112] H. Wang, L. Song, A. Lee, F. Laird, P.C. Wong, H.K. Lee, Mossy fiber long-term
potentiation deficits in BACE1 knock-outs can be rescued by activation of
alpha7 nicotinic acetylcholine receptors, J. Neurosci. 30 (2010) 13808–13813.
[113] H.Y. Wang, D.H. Lee, C.B. Davis, R.P. Shank, Amyloid peptide Abeta(1-42)
binds selectively and with picomolar affinity to alpha7 nicotinic
acetylcholine receptors, J. Neurochem. 75 (2000) 1155–1161.
[114] Y. Wang, C. Xiao, T. Indersmitten, R. Freedman, S. Leonard, H.A. Lester, The
duplicated alpha7 subunits assemble and form functional nicotinic receptors
with the full-length alpha7, J. Biol. Chem. 289 (2014) 26451–26463.
[115] M.G. Weisskopf, R.A. Nicoll, Presynaptic changes during mossy fibre LTP
revealed by NMDA receptor-mediated synaptic responses, Nature 376 (1995)
256–259.
[116] P.J. Welsby, M.J. Rowan, R. Anwyl, Intracellular mechanisms underlying the
nicotinic enhancement of LTP in the rat dentate gyrus, Eur. J. Neurosci. 29
(2009) 65–75.
[117] T. Yaguchi, T. Nagata, T. Nishizaki, Dilinoleoylphosphatidylcholine
ameliorates scopolamine-induced impairment of spatial learning and
memory by targeting alpha7 nicotinic ACh receptors, Life Sci. 84 (2009)
263–266.
[118] J.L. Yakel, Nicotinic ACh receptors in the hippocampus: role in excitability and
plasticity, Nicotine Tob. Res. 14 (2012) 1249–1257.
[119] J.L. Yakel, Cholinergic receptors: functional role of nicotinic ACh receptors in
brain circuits and disease, Pflugers Arch. 465 (2013) 441–450.
[120] F. Yi, E. Catudio-Garrett, R. Gabriel, M. Wilhelm, F. Erdelyi, G. Szabo, K.
Deisseroth, J. Lawrence, Hippocampal cholinergic interneurons visualized
with the choline acetyltransferase promoter: anatomical distribution,
intrinsic membrane properties, neurochemical characteristics, and capacity
for cholinergic modulation, Front. Synaptic Neurosci. 7 (2015) 4.
[121] J.W. Young, N. Crawford, J.S. Kelly, L.E. Kerr, H.M. Marston, C. Spratt, K.
Finlayson, J. Sharkey, Impaired attention is central to the cognitive deficits
observed in alpha 7 deficient mice, Eur. Neuropsychopharmacol. 17 (2007)
145–155.
[122] C.R. Yu, L.W. Role, Functional contribution of the alpha7 subunit to multiple
subtypes of nicotinic receptors in embryonic chick sympathetic neurones, J.
Physiol. 509 (Pt 3) (1998) 651–665.
[123] S. Zappettini, M. Grilli, A. Salamone, E. Fedele, M. Marchi, Pre-synaptic
nicotinic receptors evoke endogenous glutamate and aspartate release from
hippocampal synaptosomes by way of distinct coupling mechanisms, Br. J.
Pharmacol. 161 (2010) 1161–1171.
[124] C. Zhong, C. Du, M. Hancock, M. Mertz, D.A. Talmage, L.W. Role, Presynaptic
type III neuregulin 1 is required for sustained enhancement of hippocampal
transmission by nicotine and for axonal targeting of alpha7 nicotinic
acetylcholine receptors, J. Neurosci. 28 (2008) 9111–9116.
[125] C. Zhong, D.A. Talmage, L.W. Role, Nicotine elicits prolonged calcium
signaling along ventral hippocampal axons, PLoS One 8 (2013) e82719.